Publications by authors named "David Y Hui"

108 Publications

Apolipoprotein E receptor 2 deficiency decreases endothelial adhesion of monocytes and protects against autoimmune encephalomyelitis.

Sci Immunol 2021 Aug;6(62)

Department of Molecular Genetics, University of Texas (UT) Southwestern Medical Center, Dallas, TX, USA.

Under normal conditions, the blood-brain barrier effectively regulates the passage of immune cells into the central nervous system (CNS). However, under pathological conditions such as multiple sclerosis (MS), leukocytes, especially monocytes, infiltrate the CNS where they promote inflammatory demyelination, resulting in paralysis. Therapies targeting the immune cells directly and preventing leukocyte infiltration exist for MS but may compromise the immune system. Here, we explore how apolipoprotein E receptor 2 (ApoER2) regulates vascular adhesion and infiltration of monocytes during inflammation. We induced experimental autoimmune encephalitis in ApoER2 knockout mice and in mice carrying a loss-of-function mutation in the ApoER2 cytoplasmic domain. In both models, paralysis and neuroinflammation were largely abolished as a result of greatly diminished monocyte adherence due to reduced expression of adhesion molecules on the endothelial surface. Our findings expand our mechanistic understanding of the vascular barrier, the regulation of inflammation and vascular permeability, and the therapeutic potential of ApoER2-targeted therapies.
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http://dx.doi.org/10.1126/sciimmunol.abd0931DOI Listing
August 2021

Distinct pro-inflammatory properties of myeloid cell-derived apolipoprotein E2 and E4 in atherosclerosis promotion.

J Biol Chem 2021 Aug 21;297(3):101106. Epub 2021 Aug 21.

Department of Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. Electronic address:

Polymorphisms in the apolipoprotein E (apoE) gene are risk factors for chronic inflammatory diseases including atherosclerosis. The gene product apoE is synthesized in many cell types and has both lipid transport-dependent and lipid transport-independent functions. Previous studies have shown that apoE expression in myeloid cells protects against atherogenesis in hypercholesterolemic ApoE mice. However, the mechanism of this protection is still unclear. Using human APOE gene replacement mice as models, this study showed that apoE2 and apoE4 expressed endogenously in myeloid cells enhanced the inflammatory response via mechanisms independent of plasma lipoprotein transport. The data revealed that apoE2-expressing myeloid cells contained higher intracellular cholesterol levels because of impaired efflux, causing increasing inflammasome activation and myelopoiesis. In contrast, intracellular cholesterol levels were not elevated in apoE4-expressing myeloid cells, and its proinflammatory property was found to be independent of inflammasome signaling and related to enhanced oxidative stress. When ApoE mice were reconstituted with bone marrow from various human APOE gene replacement mice, effective reduction of atherosclerosis was observed with marrow cells obtained from APOE3 but not APOE2 and APOE4 gene replacement mice. Taken together, these results documented that apoE2 and apoE4 expression in myeloid cells promotes inflammation via distinct mechanisms and promotes atherosclerosis in a plasma lipoprotein transport-independent manner.
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http://dx.doi.org/10.1016/j.jbc.2021.101106DOI Listing
August 2021

Protein Phosphatase 2A Activation via ApoER2 in Trophoblasts Drives Preeclampsia in a Mouse Model of the Antiphospholipid Syndrome.

Circ Res 2021 Aug 18. Epub 2021 Aug 18.

Pediatrics, University of Texas Southwestern Medical Center, UNITED STATES.

Preeclampsia (PE) is a potentially life-threatening, placenta-based hypertensive disorder during pregnancy, and the antiphospholipid syndrome (APS) frequently leads to PE. APS pregnancies are also complicated by fetal demise and intrauterine growth restriction (IUGR). Here we determined how the circulating antiphospholipid antibodies (aPL) characteristic of APS alter placental trophoblast function to cause PE and also endanger the fetus. Experiments were performed in mice, in cultured human trophoblasts, and in human placenta samples. Effects of aPL and IgG from healthy subjects were compared. Based on prior findings in culture, in vivo studies were done in mice deficient in apolipoprotein E receptor 2 (ApoER2) in trophoblasts. Endpoints in tissues and cells were determined by enzymatic assay, Q-PCR, ELISA or immunoblotting. Whereas in wild-type mice aPL caused maternal hypertension and proteinuria, fetal demise and IUGR, mice lacking trophoblast ApoER2 were protected. In culture aPL attenuated trophoblast proliferation and migration via an ApoER2-related protein complex comprised of the protein phosphatase PP2A, Dab2, and JIP4. Via trophoblast ApoER2 in mice and in culture, aPL stimulated PP2A activity, leading to MMP14 and HIF1alpha upregulation and increased soluble endoglin (sEng) production. HIF1alpha and sEng upregulation was related to PP2A desphosphorylation of PHD2. In mice PP2A inhibition prevented aPL-induced maternal hypertension and proteinuria, and fetal demise and IUGR. Placentas from APS patients displayed PP2A hyperactivation, PHD2 dephosphorylation and HIF1α upregulation, and these findings were generalizable to placentas of women with PE from causes other from APS. In APS pregnancies trophoblasts are the critical cell target of aPL, and via ApoER2-dependent PP2A activation, aPL cause PE through MMP14 upregulation and PHD2 dephosphorylation leading to HIF1 and sEng upregulation. Moreover, parallel processes may be operative in PE in non-APS patients. Interventions targeting PP2A may provide novel means to combat APS-related PE and PE unrelated to APS.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.318941DOI Listing
August 2021

Chronic angiotensin receptor activation promotes hepatic triacylglycerol accumulation during an acute glucose challenge in obese-insulin-resistant OLETF rats.

Endocrine 2021 Jul 29. Epub 2021 Jul 29.

School of Natural Sciences, University of California, Merced, CA, USA.

Purpose: Angiotensin receptor blockers (ARBs) can ameliorate metabolic syndrome (MetS)-associated dyslipidemia, hepatic steatosis, and glucose intolerance, suggesting that angiotensin receptor (AT1) over-activation contributes to impaired lipid and glucose metabolism, which is characteristic of MetS. The aim of this study was to evaluate changes in the lipid profile and proteins of fatty acid uptake, triacylglycerol (TAG) synthesis, and β-oxidation to better understand the links between AT1 overactivation and non-alcoholic fatty liver disease (NAFLD) during MetS.

Methods: Four groups of 25-week-old-rats were used: (1) untreated LETO, (2) untreated OLETF, (3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 weeks) and (4) OLETF ± ARB (MINUS; 10 mg olmesartan/kg/d × 4 weeks, then removed until dissection). To investigate the dynamic shifts in metabolism, animals were dissected after an oral glucose challenge (fasting, 3 and 6 h post-glucose).

Results: Compared to OLETF, plasma total cholesterol and TAG remained unchanged in ARB. However, liver TAG was 55% lesser in ARB than OLETF, and remained lower throughout the challenge. Basal CD36 and ApoB were 28% and 29% lesser, respectively, in ARB than OLETF. PRDX6 abundance in ARB was 45% lesser than OLETF, and it negatively correlated with liver TAG in ARB.

Conclusions: Chronic blockade of AT1 protects the liver from TAG accumulation during glucose overload. This may be achieved by modulating NEFA uptake and increasing TAG export via ApoB. Our study highlights the contributions of AT1 signaling to impaired hepatic substrate metabolism and the detriments of a high-glucose load and its potential contribution to steatosis during MetS.
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http://dx.doi.org/10.1007/s12020-021-02834-7DOI Listing
July 2021

LDL receptor-related protein 1 and its interacting partners in tissue homeostasis.

Curr Opin Lipidol 2021 Oct;32(5):301-307

Department of Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Purpose Of Review: LDL receptor-related protein 1 (LRP1) is a multifunctional protein with endocytic and signal transduction properties due to its interaction with numerous extracellular ligands and intracellular proteins. This brief review highlights key developments in identifying novel functions of LRP1 in liver, lung, and the central nervous system in disease pathogenesis.

Recent Findings: In hepatocytes, LRP1 complexes with phosphatidylinositol 4-phosphate 5-kinase-1 and its related protein to maintain intracellular levels of phosphatidylinositol (4,5) bisphosphate and preserve lysosome and mitochondria integrity. In contrast, in smooth muscle cells, macrophages, and endothelial cells, LRP1 interacts with various different extracellular ligands and intracellular proteins in a tissue-dependent and microenvironment-dependent manner to either enhance or suppress inflammation, disease progression or resolution. Similarly, LRP1 expression in astrocytes and oligodendrocyte progenitor cells regulates cell differentiation and maturation in a developmental-dependent manner to modulate neurogenesis, gliogenesis, and white matter repair after injury.

Summary: LRP1 modulates metabolic disease manifestation, inflammation, and differentiation in a cell-dependent, time-dependent, and tissue-dependent manner. Whether LRP1 expression is protective or pathogenic is dependent on its interaction with specific ligands and intracellular proteins, which in turn is dependent on the cell type and the microenvironment where these cells reside.
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http://dx.doi.org/10.1097/MOL.0000000000000776DOI Listing
October 2021

Hepatic LDL receptor-related protein-1 deficiency alters mitochondrial dynamics through phosphatidylinositol 4,5-bisphosphate reduction.

J Biol Chem 2021 Jan-Jun;296:100370. Epub 2021 Feb 3.

Department of Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. Electronic address:

The LDL receptor-related protein 1 (LRP1) is a multifunctional transmembrane protein with endocytosis and signal transduction functions. Previous studies have shown that hepatic LRP1 deficiency exacerbates diet-induced steatohepatitis and insulin resistance via mechanisms related to increased lysosome and mitochondria permeability and dysfunction. The current study examined the impact of LRP1 deficiency on mitochondrial function in the liver. Hepatocytes isolated from liver-specific LRP1 knockout (hLrp1) mice showed reduced oxygen consumption compared with control mouse hepatocytes. The mitochondria in hLrp1 mouse livers have an abnormal morphology and their membranes contain significantly less anionic phospholipids, including lower levels of phosphatidylethanolamine and cardiolipin that increase mitochondrial fission and impair fusion. Additional studies showed that LRP1 complexes with phosphatidylinositol 4-phosphate 5-kinase like protein-1 (PIP5KL1) and phosphatidylinositol 4-phosphate 5-kinase-1β (PIP5K1β). The absence of LRP1 reduces the levels of both PIP5KL1 and PIP5K1β in the plasma membrane and also lowers phosphatidylinositol(4,5) bisphosphate (PI(4,5)P) levels in hepatocytes. These data indicate that LRP1 recruits PIP5KL1 and PIP5K1β to the plasma membrane for PI(4,5)P biosynthesis. The lack of LRP1 reduces lipid kinase expression, leading to lower PI(4,5)P levels, thereby decreasing the availability of this lipid metabolite in the cardiolipin biosynthesis pathway to cause cardiolipin reduction and the impairment in mitochondria homeostasis. Taken together, the current study identifies another signaling mechanism by which LRP1 regulates cell functions: binding and recruitment of PIP5KL1 and PIP5K1β to the membrane for PI(4,5)P synthesis. In addition, it highlights the importance of this mechanism for maintaining the integrity and functions of intracellular organelles.
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http://dx.doi.org/10.1016/j.jbc.2021.100370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949165PMC
August 2021

Mutation in the distal NPxY motif of LRP1 alleviates dietary cholesterol-induced dyslipidemia and tissue inflammation.

J Lipid Res 2020 Dec 15;62:100012. Epub 2020 Dec 15.

Department of Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Electronic address:

The impairment of LDL receptor-related protein-1 (LRP1) in numerous cell types is associated with obesity, diabetes, and fatty liver disease. Here, we compared the metabolic phenotype of C57BL/6J wild-type and LRP1 knock-in mice carrying an inactivating mutation in the distal NPxY motif after feeding a low-fat diet or high-fat (HF) diet with cholesterol supplementation (HFHC) or HF diet without cholesterol supplementation. In response to HF feeding, both groups developed hyperglycemia, hyperinsulinemia, hyperlipidemia, increased adiposity, and adipose tissue inflammation and liver steatosis. However, LRP1 NPxY mutation prevents HFHC diet-induced hypercholesterolemia, reduces adipose tissue and brain inflammation, and limits liver progression to steatohepatitis. Nevertheless, this mutation does not protect against HFHC diet-induced insulin resistance. The selective metabolic improvement observed in HFHC diet-fed LRP1 NPxY mutant mice is due to an apparent increase of hepatic LDL receptor levels, leading to an elevated rate of plasma lipoprotein clearance and lower hepatic cholesterol levels. The unique metabolic phenotypes displayed by LRP1 NPxY mutant mice indicate an LRP1-cholesterol axis in modulating tissue inflammation. The LRP1 NPxY mutant mouse phenotype differs from phenotypes observed in mice with tissue-specific LRP1 inactivation, thus highlighting the importance of an integrative approach to evaluate how global LRP1 dysfunction contributes to metabolic disease development.
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http://dx.doi.org/10.1194/jlr.RA120001141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859857PMC
December 2020

Bacille-Calmette-Guérin Infection Aggravates Atherosclerosis.

Front Immunol 2020 18;11:607957. Epub 2020 Dec 18.

Metabolic Diseases Research Center, Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH, United States.

Tuberculosis has been associated with increased risk of atherosclerotic cardiovascular disease. To examine whether mycobacterial infection exacerbates atherosclerosis development in experimental conditions, we infected low-density lipoprotein receptor knockout ( ) mice with Bacille-Calmette-Guérin (BCG), an attenuated strain of the complex. Twelve-week old male mice were infected with BCG (0.3-3.0x10 colony-forming units) via the intranasal route. Mice were subsequently fed a western-type diet containing 21% fat and 0.2% cholesterol for up to 16 weeks. Age-matched uninfected mice fed with an identical diet served as controls. Atherosclerotic lesions in aorta were examined using Oil Red O staining. Changes induced by BCG infection on the immunophenotyping profile of circulating T lymphocytes and monocytes were assessed using flow cytometry. BCG infection increased atherosclerotic lesions in aorta after 8 weeks (plaque ratio; 0.021±0.01 vs. 0.013±0.01; = 0.011) and 16 weeks (plaque ratio, 0.15±0.13 vs. 0.06±0.02; = 0.003). No significant differences in plasma cholesterol or triglyceride levels were observed between infected and uninfected mice. Compared to uninfected mice, BCG infection increased systemic CD4/CD8 T cell ratio and the proportion of Ly6C non-classical monocytes at weeks 8 and 16. Aortic plaque ratios correlated with CD4/CD8 T cell ratios (Spearman's rho = 0.498; = 0.001) and the proportion of Ly6C non-classical monocytes (Spearman's rho = 0.629; < 0.001) at week 16. In conclusion, BCG infection expanded the proportion of CD4 T cell and Ly6C monocytes, and aggravated atherosclerosis formation in the aortas of hyperlipidemic mice. Our results indicate that mycobacterial infection is capable of enhancing atherosclerosis development.
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http://dx.doi.org/10.3389/fimmu.2020.607957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775372PMC
June 2021

Mice lacking global Stap1 expression do not manifest hypercholesterolemia.

BMC Med Genet 2020 11 23;21(1):234. Epub 2020 Nov 23.

Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, OH, USA.

Background: Autosomal dominant familial hypercholesterolemia (ADH; MIM#143890) is one of the most common monogenic disorders characterized by elevated circulatory LDL cholesterol. Initial studies in humans with ADH identified a potential relationship with variants of the gene encoding signal transducing adaptor family member protein 1 (STAP1; MIM#604298). However, subsequent studies have been contradictory. In this study, mice lacking global Stap1 expression (Stap1) were characterized under standard chow and a 42% kcal western diet (WD).

Methods: Mice were studied for changes in different metabolic parameters before and after a 16-week WD regime. Growth curves, body fats, circulatory lipids, parameters of glucose homeostasis, and liver architecture were studied for comparisons.

Results: Surprisingly, Stap1 mice fed the 16-week WD demonstrated no marked differences in any of the metabolic parameters compared to Stap1 mice. Furthermore, hepatic architecture and cholesterol content in FPLC-isolated lipoprotein fractions also remained comparable to wild-type mice.

Conclusion: These results strongly suggest that STAP1 does not alter lipid levels, that a western diet did not exacerbate a lipid disorder in Stap1 deficient mice and support the contention that it is not causative for hyperlipidemia in ADH patients. These results support other published studies also questioning the role of this locus in human hypercholesterolemia.
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http://dx.doi.org/10.1186/s12881-020-01176-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685646PMC
November 2020

Distinct Influence of Hypercaloric Diets Predominant with Fat or Fat and Sucrose on Adipose Tissue and Liver Inflammation in Mice.

Molecules 2020 Sep 23;25(19). Epub 2020 Sep 23.

Department of Pathology, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.

Overfeeding of a hypercaloric diet leads to obesity, diabetes, chronic inflammation, and fatty liver disease. Although limiting fat or carbohydrate intake is the cornerstone for obesity management, whether lowering fat or reducing carbohydrate intake is more effective for health management remains controversial. This study used murine models to determine how dietary fat and carbohydrates may influence metabolic disease manifestation. Age-matched C57BL/6J mice were fed 2 hypercaloric diets with similar caloric content, one with very high fat and low carbohydrate content (VHF) and the other with moderately high fat levels with high sucrose content (HFHS) for 12 weeks. Both groups gained more weight and displayed hypercholesterolemia, hyperglycemia, hyperinsulinemia, and liver steatosis compared to mice fed a normal low-fat (LF) diet. Interestingly, the VHF-fed mice showed a more robust adipose tissue inflammation compared to HFHS-fed mice, whereas HFHS-fed mice showed liver fibrosis and inflammation that was not observed in VHF-fed mice. Taken together, these results indicate macronutrient-specific tissue inflammation with excess dietary fat provoking adipose tissue inflammation, whereas moderately high dietary fat with extra sucrose is necessary and sufficient for hepatosteatosis advancement to steatohepatitis. Hence, liver and adipose tissues respond to dietary fat and sucrose in opposite manners, yet both macronutrients are contributing factors to metabolic diseases.
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http://dx.doi.org/10.3390/molecules25194369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584000PMC
September 2020

Generating Multiscale Amorphous Molecular Structures Using Deep Learning: A Study in 2D.

J Phys Chem Lett 2020 Oct 24;11(20):8532-8537. Epub 2020 Sep 24.

Department of Chemistry, McGill University, 801 Sherbrooke Street W, Montreal, Quebec H3A 0B8, Canada.

Amorphous molecular assemblies appear in a vast array of systems: from living cells to chemical plants and from everyday items to new devices. The absence of long-range order in amorphous materials implies that precise knowledge of their underlying structures throughout is needed to rationalize and control their properties at the mesoscale. Standard computational simulations suffer from exponentially unfavorable scaling of the required compute with system size. We present a method based on deep learning that leverages the finite range of structural correlations for an autoregressive generation of disordered molecular aggregates up to arbitrary size from small-scale computational or experimental samples. We benchmark performance on self-assembled nanoparticle aggregates and proceed to simulate monolayer amorphous carbon with atomistic resolution. This method bridges the gap between the nanoscale and mesoscale simulations of amorphous molecular systems.
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http://dx.doi.org/10.1021/acs.jpclett.0c02535DOI Listing
October 2020

Hepatic HAX-1 inactivation prevents metabolic diseases by enhancing mitochondrial activity and bile salt export.

J Biol Chem 2020 04 20;295(14):4631-4646. Epub 2020 Feb 20.

Department of Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237

Increasing hepatic mitochondrial activity through pyruvate dehydrogenase and elevating enterohepatic bile acid recirculation are promising new approaches for metabolic disease therapy, but neither approach alone can completely ameliorate disease phenotype in high-fat diet-fed mice. This study showed that diet-induced hepatosteatosis, hyperlipidemia, and insulin resistance can be completely prevented in mice with liver-specific HCLS1-associated protein X-1 (HAX-1) inactivation. Mechanistically, we showed that HAX-1 interacts with inositol 1,4,5-trisphosphate receptor-1 (InsP3R1) in the liver, and its absence reduces InsP3R1 levels, thereby improving endoplasmic reticulum-mitochondria calcium homeostasis to prevent excess calcium overload and mitochondrial dysfunction. As a result, HAX-1 ablation activates pyruvate dehydrogenase and increases mitochondria utilization of glucose and fatty acids to prevent hepatosteatosis, hyperlipidemia, and insulin resistance. In contrast to the reduction of InsP3R1 levels, hepatic HAX-1 deficiency increases bile salt exporter protein levels, thereby promoting enterohepatic bile acid recirculation, leading to activation of bile acid-responsive genes in the intestinal ileum to augment insulin sensitivity and of cholesterol transport genes in the liver to suppress hyperlipidemia. The dual mechanisms of increased mitochondrial respiration and enterohepatic bile acid recirculation due to improvement of endoplasmic reticulum-mitochondria calcium homeostasis with hepatic HAX-1 inactivation suggest that this may be a potential therapeutic target for metabolic disease intervention.
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http://dx.doi.org/10.1074/jbc.RA119.012361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135988PMC
April 2020

Prefrontal Cortex Regulates Chronic Stress-Induced Cardiovascular Susceptibility.

J Am Heart Assoc 2019 12 14;8(24):e014451. Epub 2019 Dec 14.

Biomedical Sciences Colorado State University Fort Collins CO.

Background The medial prefrontal cortex is necessary for appropriate appraisal of stressful information, as well as coordinating visceral and behavioral processes. However, prolonged stress impairs medial prefrontal cortex function and prefrontal-dependent behaviors. Additionally, chronic stress induces sympathetic predominance, contributing to health detriments associated with autonomic imbalance. Previous studies identified a subregion of rodent prefrontal cortex, infralimbic cortex (IL), as a key regulator of neuroendocrine-autonomic integration after chronic stress, suggesting that IL output may prevent chronic stress-induced autonomic imbalance. In the current study, we tested the hypothesis that the IL regulates hemodynamic, vascular, and cardiac responses to chronic stress. Methods and Results A viral-packaged small interfering RNA construct was used to knockdown vesicular glutamate transporter 1 (vGluT1) and reduce glutamate packaging and release from IL projection neurons. Male rats were injected with a vGluT1 small interfering RNA-expressing construct or GFP (green fluorescent protein) control into the IL and then remained as unstressed controls or were exposed to chronic variable stress. IL vGluT1 knockdown increased heart rate and mean arterial pressure reactivity, while chronic variable stress increased chronic mean arterial pressure only in small interfering RNA-treated rats. In another cohort, chronic variable stress and vGluT1 knockdown interacted to impair both endothelial-dependent and endothelial-independent vasoreactivity ex vivo. Furthermore, vGluT1 knockdown and chronic variable stress increased histological markers of fibrosis and hypertrophy. Conclusions Knockdown of glutamate release from IL projection neurons indicates that these cells are necessary to prevent the enhanced physiological responses to stress that promote susceptibility to cardiovascular pathophysiology. Ultimately, these findings provide evidence for a neurobiological mechanism mediating the relationship between stress and poor cardiovascular health outcomes.
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http://dx.doi.org/10.1161/JAHA.119.014451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951062PMC
December 2019

ApoER2 (Apolipoprotein E Receptor-2) Deficiency Accelerates Smooth Muscle Cell Senescence via Cytokinesis Impairment and Promotes Fibrotic Neointima After Vascular Injury.

Arterioscler Thromb Vasc Biol 2019 10 15;39(10):2132-2144. Epub 2019 Aug 15.

From the Department of Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, OH.

Objective: Genome-wide studies showed that mutation in apoER2 (apolipoprotein E receptor-2) is additive with ε4 polymorphism in the gene on cardiovascular disease risk in humans. ApoE or apoER2 deficiency also accelerates atherosclerosis lesion necrosis in hypercholesterolemic mice and promotes neointima formation after vascular injury. This study tests the hypothesis that apoE and apoER2 modulate vascular occlusive diseases through distinct mechanisms. Approach and Results: Carotid endothelial denudation induced robust neointima formation in both and apoER2-deficient mice. The intima in mice was rich in smooth muscle cells, but the intima in mice was cell-poor and rich in extracellular matrix. Vascular smooth muscle cells isolated from mice were hyperplastic whereas smooth muscle cells showed reduced proliferation but responded robustly to TGF (transforming growth factor)-β-induced fibronectin synthesis indicative of a senescence-associated secretory phenotype, which was confirmed by increased β-galactosidase activity, p16 immunofluorescence, and number of multinucleated cells. Western blot analysis of cell cycle-associated proteins showed that apoER2 deficiency promotes cell cycle arrest at the metaphase/anaphase. Coimmunoprecipitation experiments revealed that apoER2 interacts with the catalytic subunit of protein phosphatase 2A. In the absence of apoER2, PP2A-C (protein phosphatase 2A catalytic subunit) failed to interact with CDC20 (cell-division cycle protein 20) thus resulting in inactive anaphase-promoting complex and impaired cell cycle exit.

Conclusions: This study showed that apoER2 participates in APC (anaphase-promoting complex)/CDC20 complex formation during mitosis, and its absence impedes cytokinesis abscission thereby accelerating premature cell senescence and vascular disease. This mechanism is distinct from apoE deficiency, which causes smooth muscle cell hyperplasia to accelerate vascular disease.
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http://dx.doi.org/10.1161/ATVBAHA.119.313194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761011PMC
October 2019

Enhancer of zeste homolog 2 (EZH2) regulates adipocyte lipid metabolism independent of adipogenic differentiation: Role of apolipoprotein E.

J Biol Chem 2019 05 10;294(21):8577-8591. Epub 2019 Apr 10.

Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia 30912; Department of Medicine (Division of Cardiology), Medical College of Georgia at Augusta University, Augusta, Georgia 30912. Electronic address:

Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator that plays a key role in cell differentiation and oncogenesis, was reported to promote adipogenic differentiation by catalyzing trimethylation of histone 3 lysine 27. However, inhibition of EZH2 induced lipid accumulation in certain cancer and hepatocyte cell lines. To address this discrepancy, we investigated the role of EZH2 in adipogenic differentiation and lipid metabolism using primary human and mouse preadipocytes and adipose-specific EZH2 knockout (KO) mice. We found that the EZH2-selective inhibitor GSK126 induced lipid accumulation in human adipocytes, without altering adipocyte differentiation marker gene expression. Moreover, adipocyte-specific EZH2 KO mice, generated by crossing EZH2 floxed mice with adiponectin-Cre mice, displayed significantly increased body weight, adipose tissue mass, and adipocyte cell size and reduced very low-density lipoprotein (VLDL) levels, as compared with littermate controls. These phenotypic alterations could not be explained by differences in feeding behavior, locomotor activity, metabolic energy expenditure, or adipose lipolysis. In addition, human adipocytes treated with either GSK126 or vehicle exhibited comparable rates of glucose-stimulated triglyceride accumulation and fatty acid uptake. Mechanistically, lipid accumulation induced by GSK126 in adipocytes was lipoprotein-dependent, and EZH2 inhibition or gene deletion promoted lipoprotein-dependent lipid uptake concomitant with up-regulated apolipoprotein E () gene expression. Deletion of blocked the effects of GSK126 to promote lipoprotein-dependent lipid uptake in murine adipocytes. Collectively, these results indicate that EZH2 inhibition promotes lipoprotein-dependent lipid accumulation via inducing expression in adipocytes, suggesting a novel mechanism of lipid regulation by EZH2.
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http://dx.doi.org/10.1074/jbc.RA118.006871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544862PMC
May 2019

Therapeutic reduction of lysophospholipids in the digestive tract recapitulates the metabolic benefits of bariatric surgery and promotes diabetes remission.

Mol Metab 2018 10 26;16:55-64. Epub 2018 Jul 26.

Department of Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45237, USA. Electronic address:

Objective: Obesity and obesity-related metabolic disorders are major health problems worldwide. The most effective obesity intervention is bariatric surgery. This study tested the hypothesis that bariatric surgery alters phospholipid metabolism in the gastrointestinal tract to favor a metabolically healthy gut microbiota profile and therapeutic intervention of phospholipid metabolism in the gastrointestinal may have similar metabolic benefits.

Methods: The first study compared plasma levels of the bioactive lipid metabolites lysophospholipid and trimethylamine N-oxide (TMAO) as well as gut microbiota profile in high fat/carbohydrate (HFHC) diet-fed C57BL/6 mice with or without vertical sleeve gastrectomy (VSG) and in Pla2g1b mice with group 1B phospholipase A gene inactivation. The second study examined the effectiveness of the non-absorbable secretory phospholipase A inhibitor methyl indoxam to reverse hyperglycemia and hyperlipidemia in HFHC diet-fed C57BL/6 mice after diabetes onset.

Results: Both bariatric surgery and PLA2G1B inactivation were shown to reduce lysophospholipid content in the gastrointestinal tract, resulting in resistance to HFHC diet-induced alterations of the gut microbiota, reduction of the cardiovascular risk factors hyperlipidemia and TMAO, decreased adiposity, and prevention of HFHC diet-induced diabetes. Importantly, treatment of wild type mice with methyl indoxam after HFHC diet-induced onset of hyperlipidemia and hyperglycemia effectively restored normal plasma lipid and glucose levels and replicated the metabolic benefits of VSG surgery with diabetes remission and TMAO reduction.

Conclusion: These results provided pre-clinical evidence that PLA2G1B inhibition in the digestive tract may be a viable alternative option to bariatric surgery for obesity and obesity-related cardiometabolic disorder intervention.
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http://dx.doi.org/10.1016/j.molmet.2018.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158127PMC
October 2018

Group 1B phospholipase A in metabolic and inflammatory disease modulation.

Authors:
David Y Hui

Biochim Biophys Acta Mol Cell Biol Lipids 2019 06 9;1864(6):784-788. Epub 2018 Jul 9.

Department of Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA; Department of Pathology, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, 2120 E. Galbraith Road, Cincinnati, OH 45237, United States. Electronic address:

The group 1B phospholipase A (PLA2G1B) is a secreted phospholipase that catalyzes the hydrolytic removal of the sn-2 fatty acyl moiety from phospholipids. This enzyme is synthesized most abundantly in the pancreas and is also expressed in the lung. The first part of this review article focuses on the role of pancreatic-derived PLA2G1B in mediating lipid absorption and discusses how the PLA2G1B-derived metabolic product contributes to cardiometabolic diseases, including obesity, hyperinsulinemia, hyperlipidemia, and atherosclerosis. The anti-helminth properties of PLA2G1B will also be discussed. The second part of this review will focus on PLA2G1B expressed in the lung, and in vitro data suggest that how this enzyme may modulate lung inflammation via both hydrolytic activity-dependent and -dependent mechanisms. Finally, recent studies revealing a relationship between PLA2G1B and cancer will also be discussed. This article is part of a Special Issue entitled Novel functions of phospholipase A2 Guest Editors: Makoto Murakami and Gerard Lambeau.
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http://dx.doi.org/10.1016/j.bbalip.2018.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328335PMC
June 2019

Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans.

Arterioscler Thromb Vasc Biol 2018 07 31;38(7):1440-1453. Epub 2018 May 31.

From the Department of Pediatrics, Section of Molecular Genetics, University Medical Centre Groningen, University of Groningen, The Netherlands (F.O., J.C.W., B.v.d.S., J.A.K.)

Objective: Studies into the role of LRP1 (low-density lipoprotein receptor-related protein 1) in human lipid metabolism are scarce. Although it is known that a common variant in (rs116133520) is significantly associated with HDL-C (high-density lipoprotein cholesterol), the mechanism underlying this observation is unclear. In this study, we set out to study the functional effects of 2 rare variants identified in subjects with extremely low HDL-C levels.

Approach And Results: In 2 subjects with HDL-C below the first percentile for age and sex and moderately elevated triglycerides, we identified 2 rare variants in : p.Val3244Ile and p.Glu3983Asp. Both variants decrease LRP1 expression and stability. We show in a series of translational experiments that these variants culminate in reduced trafficking of ABCA1 (ATP-binding cassette A1) to the cell membrane. This is accompanied by an increase in cell surface expression of SR-B1 (scavenger receptor class B type 1). Combined these effects may contribute to low HDL-C levels in our study subjects. Supporting these findings, we provide epidemiological evidence that rs116133520 is associated with apo (apolipoprotein) A1 but not with apoB levels.

Conclusions: This study provides the first evidence that rare variants in are associated with changes in human lipid metabolism. Specifically, this study shows that LRP1 may affect HDL metabolism by virtue of its effect on both ABCA1 and SR-B1.
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http://dx.doi.org/10.1161/ATVBAHA.117.310309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023722PMC
July 2018

Low-density lipoprotein receptor-related protein-1 dysfunction synergizes with dietary cholesterol to accelerate steatohepatitis progression.

J Biol Chem 2018 06 11;293(25):9674-9684. Epub 2018 May 11.

Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237 and

Reduced low-density lipoprotein receptor-related protein-1 (LRP1) expression in the liver is associated with poor prognosis of liver cirrhosis and hepatocellular carcinoma. Previous studies have shown that hepatic LRP1 deficiency exacerbates palmitate-induced steatosis and toxicity and also promotes high-fat diet-induced hepatic insulin resistance and hepatic steatosis The current study examined the impact of liver-specific LRP1 deficiency on disease progression to steatohepatitis. mice with normal LRP1 expression and mice with hepatocyte-specific LRP1 inactivation were fed a high-fat, high-cholesterol (HFHC) diet for 16 weeks. Plasma lipid levels and body weights were similar between both groups. However, the mice displayed significant increases in liver steatosis, inflammation, and fibrosis compared with the mice. Hepatocyte cell size, liver weight, and cell death, as measured by serum alanine aminotransferase levels, were also significantly increased in mice. The accelerated liver pathology observed in HFHC-fed mice was associated with reduced expression of cholesterol excretion and bile acid synthesis genes, leading to elevated immune cell infiltration and inflammation. Additional studies revealed that cholesterol loading induced significantly higher expression of genes responsible for hepatic stellate cell activation and fibrosis in hepatocytes than in hepatocytes. These results indicate that hepatic LRP1 deficiency accelerates liver disease progression by increasing hepatocyte death, thereby causing inflammation and increasing sensitivity to cholesterol-induced pro-fibrotic gene expression to promote steatohepatitis. Thus, LRP1 may be a genetic variable that dictates individual susceptibility to the effects of dietary cholesterol on liver diseases.
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http://dx.doi.org/10.1074/jbc.RA118.001952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016462PMC
June 2018

Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2-SHC1 complex formation in endothelium.

Blood 2018 05 2;131(19):2097-2110. Epub 2018 Mar 2.

Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.

In the antiphospholipid syndrome (APS), antiphospholipid antibody (aPL) recognition of β2 glycoprotein I promotes thrombosis, and preclinical studies indicate that this is due to endothelial nitric oxide synthase (eNOS) antagonism via apolipoprotein E receptor 2 (apoER2)-dependent processes. How apoER2 molecularly links these events is unknown. Here, we show that, in endothelial cells, the apoER2 cytoplasmic tail serves as a scaffold for aPL-induced assembly and activation of the heterotrimeric protein phosphatase 2A (PP2A). Disabled-2 (Dab2) recruitment to the apoER2 NPXY motif promotes the activating L309 methylation of the PP2A catalytic subunit by leucine methyl transferase-1. Concurrently, Src homology domain-containing transforming protein 1 (SHC1) recruits the PP2A scaffolding subunit to the proline-rich apoER2 C terminus along with 2 distinct regulatory PP2A subunits that mediate inhibitory dephosphorylation of Akt and eNOS. In mice, the coupling of these processes in endothelium is demonstrated to underlie aPL-invoked thrombosis. By elucidating these intricacies in the pathogenesis of APS-related thrombosis, numerous potential new therapeutic targets have been identified.
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http://dx.doi.org/10.1182/blood-2017-11-814681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946764PMC
May 2018

Epithelial-Cell-Derived Phospholipase A Group 1B Is an Endogenous Anthelmintic.

Cell Host Microbe 2017 Oct;22(4):484-493.e5

Allergy and Anti-helminth Immunity Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Immunology Discovery, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address:

Immunity to intestinal helminth infections has been well studied, but the mechanism of helminth killing prior to expulsion remains unclear. Here we identify epithelial-cell-derived phospholipase A group 1B (PLAg1B) as a host-derived endogenous anthelmintic. PLAg1B is elevated in resistant mice and is responsible for killing tissue-embedded larvae. Despite comparable activities of other essential type-2-dependent immune mechanisms, Pla2g1b mice failed to expel the intestinal helminths Heligmosomoides polygyrus or Nippostrongylus brasiliensis. Expression of Pla2g1b by epithelial cells was dependent upon intestinal microbiota, adaptive immunity, and common-gamma chain-dependent signaling. Notably, Pla2g1b was downregulated in susceptible mice and inhibited by IL-4R-signaling in vitro, uncoupling parasite killing from expulsion mechanisms. Resistance was restored in Pla2g1b mice by treating infective H. polygyrus L3 larvae with PLAg1B, which reduced larval phospholipid abundance. These findings uncover epithelial-cell-derived Pla2g1b as an essential mediator of helminth killing, highlighting a previously overlooked mechanism of anti-helminth immunity.
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http://dx.doi.org/10.1016/j.chom.2017.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644720PMC
October 2017

The good side of cholesterol: a requirement for maintenance of intestinal integrity.

Authors:
David Y Hui

J Lipid Res 2017 10 2;58(10):1935-1936. Epub 2017 Aug 2.

Department of Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, OH 45237

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http://dx.doi.org/10.1194/jlr.C079715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625116PMC
October 2017

Deficiency of LRP1 in Mature Adipocytes Promotes Diet-Induced Inflammation and Atherosclerosis-Brief Report.

Arterioscler Thromb Vasc Biol 2017 06 4;37(6):1046-1049. Epub 2017 May 4.

From the Department of Pathology, University of Cincinnati College of Medicine, OH (E.S.K., J.E.B., D.G.K., D.Y.H.); and the Division of Cardiology, Department of Medicine, Medical College of Georgia at Augusta University (N.L.W.).

Objective: Mice with adipocyte-specific inactivation of low-density lipoprotein receptor-related protein-1 (LRP1) are resistant to diet-induced obesity and hyperglycemia because of compensatory thermogenic response by muscle. However, the physiological function of LRP1 in mature adipocytes and its role in cardiovascular disease modulation are unknown. This study compared perivascular adipose tissues (PVAT) from wild-type () and adipocyte-specific LRP1 knockout () mice in modulation of atherosclerosis progression.

Approach And Results: Analysis of adipose tissues from and mice after Western diet feeding for 16 weeks revealed that, in comparison to mice, the adipocytes in mice were smaller, but their adipose tissues were more inflamed with increased monocyte-macrophage infiltration and inflammatory gene expression. The transplantation of PVAT from chow-fed and mice into the area surrounding the carotid arteries of mice before feeding the Western diet revealed a contributory role of PVAT toward hypercholesterolemia-induced atherosclerosis. Importantly, recipients of PVAT displayed a 3-fold increase in atherosclerosis compared with PVAT recipients. The increased atherosclerosis invoked by LRP1-deficient PVAT was associated with elevated monocyte-macrophage infiltration and inflammatory cytokine expression in the transplanted fat.

Conclusions: PVAT provide outside-in signals through the adventitia to modulate atherosclerotic lesion progression in response to hypercholesterolemia. Moreover, adipocytes with LRP1 deficiency are dysfunctional and more inflamed. This latter observation adds the adipose tissue to the list of anatomic sites where LRP1 expression is important to protect against diet-induced atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.117.309414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485832PMC
June 2017

A novel role for the Wnt inhibitor APCDD1 in adipocyte differentiation: Implications for diet-induced obesity.

J Biol Chem 2017 04 27;292(15):6312-6324. Epub 2017 Feb 27.

Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia 30912,

Impaired adipogenic differentiation during diet-induced obesity (DIO) promotes adipocyte hypertrophy and inflammation, thereby contributing to metabolic disease. Adenomatosis polyposis coli down-regulated 1 (APCDD1) has recently been identified as an inhibitor of Wnt signaling, a key regulator of adipogenic differentiation. Here we report a novel role for APCDD1 in adipogenic differentiation via repression of Wnt signaling and an epigenetic linkage between miR-130 and APCDD1 in DIO. APCDD1 expression was significantly up-regulated in mature adipocytes compared with undifferentiated preadipocytes in both human and mouse subcutaneous adipose tissues. siRNA-based silencing of APCDD1 in 3T3-L1 preadipocytes markedly increased the expression of Wnt signaling proteins (Wnt3a, Wnt5a, Wnt10b, LRP5, and β-catenin) and inhibited the expression of adipocyte differentiation markers (CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ)) and lipid droplet accumulation, whereas adenovirus-mediated overexpression of APCDD1 enhanced adipogenic differentiation. Notably, DIO mice exhibited reduced APCDD1 expression and increased Wnt expression in both subcutaneous and visceral adipose tissues and impaired adipogenic differentiation Mechanistically, we found that miR-130, whose expression is up-regulated in adipose tissues of DIO mice, could directly target the 3'-untranslated region of the APCDD1 gene. Furthermore, transfection of an miR-130 inhibitor in preadipocytes enhanced, whereas an miR-130 mimic blunted, adipogenic differentiation, suggesting that miR-130 contributes to impaired adipogenic differentiation during DIO by repressing APCDD1 expression. Finally, human subcutaneous adipose tissues isolated from obese individuals exhibited reduced expression of APCDD1, C/EBPα, and PPARγ compared with those from non-obese subjects. Taken together, these novel findings suggest that APCDD1 positively regulates adipogenic differentiation and that its down-regulation by miR-130 during DIO may contribute to impaired adipogenic differentiation and obesity-related metabolic disease.
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http://dx.doi.org/10.1074/jbc.M116.758078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391760PMC
April 2017

Intestinal phospholipid and lysophospholipid metabolism in cardiometabolic disease.

Authors:
David Y Hui

Curr Opin Lipidol 2016 10;27(5):507-12

Department of Pathology, Metabolic Disease Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Purpose Of Review: Phospholipids are major constituents in the intestinal lumen after meal consumption. This article highlights current literature suggesting the contributory role of intestinal phospholipid metabolism toward cardiometabolic disease manifestation.

Recent Findings: Group 1b phospholipase A2 (PLA2g1b) catalyzes phospholipid hydrolysis in the intestinal lumen. The digestive product lysophospholipid, particularly lysophosphatidylcholine (LPC), has a direct role in mediating chylomicron assembly and secretion. The LPC in the digestive tract is further catabolized into lysophosphatidic acid and choline via autotaxin-mediated and autotaxin-independent mechanisms. The LPC and lysophosphatidic acid absorbed through the digestive tract and transported to the plasma directly promote systemic inflammation and cell dysfunction, leading to increased risk of cardiovascular disease and obesity/diabetes. The choline moiety generated in the digestive tract can also be used by gut bacteria to generate trimethylamine, which is subsequently transported to the liver and oxidized into trimethylamine-N-oxide that also enhances atherosclerosis and cardiovascular abnormalities.

Summary: Products of phospholipid metabolism in the intestine through PLA2g1b and autotaxin-mediated pathways directly contribute to cardiometabolic diseases through multiple mechanisms. The implication of these studies is that therapeutic inhibition of PLA2g1b and autotaxin in the digestive tract may be a viable approach for cardiovascular and metabolic disease intervention.
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http://dx.doi.org/10.1097/MOL.0000000000000334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125253PMC
October 2016

LRP1 Protein Deficiency Exacerbates Palmitate-induced Steatosis and Toxicity in Hepatocytes.

J Biol Chem 2016 08 17;291(32):16610-9. Epub 2016 Jun 17.

Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237

LRP1 (LDL receptor-related protein-1) is a ubiquitous receptor with both cell signaling and ligand endocytosis properties. In the liver, LRP1 serves as a chylomicron remnant receptor and also participates in the transport of extracellular cathepsin D to the lysosome for prosaposin activation. The current study showed that in comparison with wild type mice, hepatocyte-specific LRP1 knock-out (hLrp1(-/-)) mice were more susceptible to fasting-induced lipid accumulation in the liver. Primary hepatocytes isolated from hLrp1(-/-) mice also accumulated more intracellular lipids and experienced higher levels of endoplasmic reticulum (ER) stress after palmitate treatment compared with similarly treated hLrp1(+/+) hepatocytes. Palmitate-treated hLrp1(-/-) hepatocytes displayed similar LC3-II levels, but the levels of p62 were elevated in comparison with palmitate-treated hLrp1(+/+) hepatocytes, suggesting that the elevated lipid accumulation in LRP1-defective hepatocytes was not due to defects in autophagosome formation but was due to impairment of lipophagic lipid hydrolysis in the lysosome. Additional studies showed increased palmitate-induced oxidative stress, mitochondrial and lysosomal permeability, and cell death in hLrp1(-/-) hepatocytes. Importantly, the elevated cell death and ER stress observed in hLrp1(-/-) hepatocytes were abrogated by E64D treatment, whereas inhibiting ER stress diminished cell death but not lysosomal permeabilization. Taken together, these results documented that LRP1 deficiency in hepatocytes promotes lipid accumulation and lipotoxicity through lysosomal-mitochondrial permeabilization and ER stress that ultimately result in cell death. Hence, LRP1 dysfunction may be a major risk factor in fatty liver disease progression.
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http://dx.doi.org/10.1074/jbc.M116.717744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974376PMC
August 2016

Red Blood Cell Dysfunction Induced by High-Fat Diet: Potential Implications for Obesity-Related Atherosclerosis.

Circulation 2015 Nov 14;132(20):1898-908. Epub 2015 Oct 14.

From Hematology/Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, OH (D.U., R.S., R.K., R.S., V.B., M.P., R.S.F., V.Y.B.); Vascular Biology Center, Georgia Regents University, Augusta, GA (T.B., S.H., T.C., D.J.F., N.L.W.); Cardiovascular Diseases, Department of Internal Medicine, College of Medicine, University of Cincinnati, OH (D.C., N.B., W.T., D.M.); Department of Nutritional Sciences, College of Allied Health Sciences, University of Cincinnati, OH (D.C., A.P.); Department of Pathology, College of Medicine, University of Cincinnati, OH (D.Y.H., W.S.D.); Biomedical Informatics and Developmental Biology / Department of Pediatrics, College of Medicine, University of Cincinnati and Cincinnati Children's Hospital and Medical Center, OH (B.J.A.); Experimental Hematology / Department of Pediatrics, College of Medicine, University of Cincinnati and Cincinnati Children's Hospital and Medical Center, OH (T.K.); Hemoshear LLC, Charlottesville, VA (D.M.); and Department of Emergency Medicine, University of Texas Southwestern Medical Center, Dallas (A.B.).

Background: High-fat diet (HFD) promotes endothelial dysfunction and proinflammatory monocyte activation, which contribute to atherosclerosis in obesity. We investigated whether HFD also induces the dysfunction of red blood cells (RBCs), which serve as a reservoir for chemokines via binding to Duffy antigen receptor for chemokines (DARC).

Methods And Results: A 60% HFD for 12 weeks, which produced only minor changes in lipid profile in C57/BL6 mice, markedly augmented the levels of monocyte chemoattractant protein-1 bound to RBCs, which in turn stimulated macrophage migration through an endothelial monolayer. Levels of RBC-bound KC were also increased by HFD. These effects of HFD were abolished in DARC(-/-) mice. In RBCs from HFD-fed wild-type and DARC(-/-) mice, levels of membrane cholesterol and phosphatidylserine externalization were increased, fostering RBC-macrophage inflammatory interactions and promoting macrophage phagocytosis in vitro. When labeled ex vivo and injected into wild-type mice, RBCs from HFD-fed mice exhibited ≈3-fold increase in splenic uptake. Finally, RBCs from HFD-fed mice induced increased macrophage adhesion to the endothelium when they were incubated with isolated aortic segments, indicating endothelial activation.

Conclusions: RBC dysfunction, analogous to endothelial dysfunction, occurs early during diet-induced obesity and may serve as a mediator of atherosclerosis. These findings may have implications for the pathogenesis of atherosclerosis in obesity, a worldwide epidemic.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.017313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772773PMC
November 2015

Role of histone deacetylase 9 in regulating adipogenic differentiation and high fat diet-induced metabolic disease.

Adipocyte 2014 Oct-Dec;3(4):333-8. Epub 2014 Dec 10.

Department of Internal Medicine; Vascular Biology Center; Georgia Regents University ; Augusta, GA USA.

Adipose tissue serves as both a storage site for excess calories and as an endocrine organ, secreting hormones such as adiponectin that promote metabolic homeostasis. In obesity, adipose tissue expands primarily by hypertrophy (enlargement of existing adipocytes) rather than hyperplasia (generation of new adipocytes via adipogenic differentiation of preadipocytes). Progressive adipocyte hypertrophy leads to inflammation, insulin resistance, dyslipidemia, and ectopic lipid deposition, the hallmark characteristics of metabolic disease. We demonstrate that during chronic high fat feeding in mice, adipogenic differentiation is impaired due to the actions of histone deacetylase 9 (HDAC9), a member of the class II family of HDACs. Mechanistically, upregulated HDAC9 expression blocks the adipogenic differentiation program during chronic high fat feeding, leading to accumulation of improperly differentiated adipocytes with diminished expression of adiponectin. These adipocytes are inefficient at storing lipid, resulting in ectopic lipid deposition in the liver. HDAC9 gene deletion prevents the detrimental effects of chronic high fat feeding on adipogenic differentiation, increases adiponectin expression, and enhances energy expenditure by promoting beige adipogenesis, thus leading to reduced body mass and improved metabolic homeostasis. HDAC9 is therefore emerging as a critical regulator of adipose tissue health and a novel therapeutic target for obesity-related disease.
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http://dx.doi.org/10.4161/adip.28814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550687PMC
August 2015

Histone Deacetylases and Cardiometabolic Diseases.

Arterioscler Thromb Vasc Biol 2015 Sep 16;35(9):1914-9. Epub 2015 Jul 16.

From the Department of Pharmacology and Toxicology (K.H.Y.) and Vascular Biology Center, Department of Medicine (K.H.Y., T.K.C., N.L.W.), Medical College of Georgia/Georgia Regents University, Augusta; and Department of Pathology, Institute for Metabolic Diseases, University of Cincinnati, OH (D.Y.H.).

Cardiometabolic disease, emerging as a worldwide epidemic, is a combination of metabolic derangements leading to type 2 diabetes mellitus and cardiovascular disease. Genetic and environmental factors are linked through epigenetic mechanisms to the pathogenesis of cardiometabolic disease. Post-translational modifications of histone tails, including acetylation and deacetylation, epigenetically alter chromatin structure and dictate cell-specific gene expression patterns. The histone deacetylase family comprises 18 members that regulate gene expression by altering the acetylation status of nucleosomal histones and by functioning as nuclear transcriptional corepressors. Histone deacetylases regulate key aspects of metabolism, inflammation, and vascular function pertinent to cardiometabolic disease in a cell- and tissue-specific manner. Histone deacetylases also likely play a role in the metabolic memory of diabetes mellitus, an important clinical aspect of the disease. Understanding the molecular, cellular, and physiological functions of histone deacetylases in cardiometabolic disease is expected to provide insight into disease pathogenesis, risk factor control, and therapeutic development.
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http://dx.doi.org/10.1161/ATVBAHA.115.305046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552588PMC
September 2015

PDZK1 prevents neointima formation via suppression of breakpoint cluster region kinase in vascular smooth muscle.

PLoS One 2015 17;10(4):e0124494. Epub 2015 Apr 17.

Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.

Scavenger receptor class B, type I (SR-BI) and its adaptor protein PDZK1 mediate responses to HDL cholesterol in endothelium. Whether the receptor-adaptor protein tandem serves functions in other vascular cell types is unknown. The current work determined the roles of SR-BI and PDZK1 in vascular smooth muscle (VSM). To evaluate possible VSM functions of SR-BI and PDZK1 in vivo, neointima formation was assessed 21 days post-ligation in the carotid arteries of wild-type, SR-BI-/- or PDZK1-/- mice. Whereas neointima development was negligible in wild-type and SR-BI-/-, there was marked neointima formation in PDZK1-/- mice. PDZK1 expression was demonstrated in primary mouse VSM cells, and compared to wild-type cells, PDZK1-/- VSM displayed exaggerated proliferation and migration in response to platelet derived growth factor (PDGF). Tandem affinity purification-mass spectrometry revealed that PDZK1 interacts with breakpoint cluster region kinase (Bcr), which contains a C-terminal PDZ binding sequence and is known to enhance responses to PDGF in VSM. PDZK1 interaction with Bcr in VSM was demonstrated by pull-down and by coimmunoprecipitation, and the augmented proliferative response to PDGF in PDZK1-/- VSM was abrogated by Bcr depletion. Furthermore, compared with wild-type Bcr overexpression, the introduction of a Bcr mutant incapable of PDZK1 binding into VSM cells yielded an exaggerated proliferative response to PDGF. Thus, PDZK1 has novel SR-BI-independent function in VSM that affords protection from neointima formation, and this involves PDZK1 suppression of VSM cell proliferation via an inhibitory interaction with Bcr.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124494PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401672PMC
April 2016
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