Publications by authors named "Aldons J Lusis"

417 Publications

β3-adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity.

J Clin Invest 2021 Nov 30. Epub 2021 Nov 30.

Department of Medicine, UCSD, La Jolla, United States of America.

The dysregulation of energy homeostasis in obesity involves multi-hormone resistance. Although leptin and insulin resistance have been well characterized, catecholamine resistance remains largely unexplored. Murine β3-adrenergic receptor expression in adipocytes is orders of magnitude higher compared to other isoforms. While resistant to classical desensitization pathways, its mRNA (Adrb3) and protein expression are dramatically downregulated after ligand exposure (homologous desensitization). β3-adrenergic receptor downregulation also occurs after high fat diet feeding, concurrent with catecholamine resistance and elevated inflammation. This downregulation is recapitulated in vitro by TNFα treatment (heterologous desensitization). Both homologous and heterologous desensitization of Adrb3 were triggered by induction of the pseudokinase TRIB1 downstream of the EPAC/RAP2A/PI-PLC pathway. TRIB1 in turn degraded the primary transcriptional activator of Adrb3, CEBPα. EPAC/RAP inhibition enhanced catecholamine-stimulated lipolysis and energy expenditure in obese mice. Moreover, adipose tissue expression of genes in this pathway correlated with body weight extremes in a cohort of genetically diverse mice, and with BMI in two independent cohorts of humans. These data implicate a new signaling axis that may explain reduced hormone-stimulated lipolysis in obesity and resistance to therapeutic interventions with β3-adrenergic receptor agonists.
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http://dx.doi.org/10.1172/JCI153357DOI Listing
November 2021

Fecal Microbiome Composition Does Not Predict Diet-Induced TMAO Production in Healthy Adults.

J Am Heart Assoc 2021 Nov 29;10(21):e021934. Epub 2021 Oct 29.

Department of Cardiovascular and Metabolic Sciences Lerner Research Institute Cleveland Clinic Cleveland OH.

Background Trimethylamine--oxide (TMAO) is a small molecule derived from the metabolism of dietary nutrients by gut microbes and contributes to cardiovascular disease. Plasma TMAO increases following consumption of red meat. This metabolic change is thought to be partly because of the expansion of gut microbes able to use nutrients abundant in red meat. Methods and Results We used data from a randomized crossover study to estimate the degree to which TMAO can be estimated from fecal microbial composition. Healthy participants received a series of 3 diets that differed in protein source (red meat, white meat, and non-meat), and fecal, plasma, and urine samples were collected following 4 weeks of exposure to each diet. TMAO was quantitated in plasma and urine, while shotgun metagenomic sequencing was performed on fecal DNA. While the cai gene cluster was weakly correlated with plasma TMAO (rho=0.17, =0.0007), elastic net models of TMAO were not improved by abundances of bacterial genes known to contribute to TMAO synthesis. A global analysis of all taxonomic groups, genes, and gene families found no meaningful predictors of TMAO. We postulated that abundances of known genes related to TMAO production do not predict bacterial metabolism, and we measured choline- and carnitine-trimethylamine lyase activity during fecal culture. Trimethylamine lyase genes were only weakly correlated with the activity of the enzymes they encode. Conclusions Fecal microbiome composition does not predict systemic TMAO because, in this case, gene copy number does not predict bacterial metabolic activity. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01427855.
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http://dx.doi.org/10.1161/JAHA.121.021934DOI Listing
November 2021

Glycogen metabolism links glucose homeostasis to thermogenesis in adipocytes.

Nature 2021 11 27;599(7884):296-301. Epub 2021 Oct 27.

Department of Medicine, University of California San Diego, San Diego, CA, USA.

Adipocytes increase energy expenditure in response to prolonged sympathetic activation via persistent expression of uncoupling protein 1 (UCP1). Here we report that the regulation of glycogen metabolism by catecholamines is critical for UCP1 expression. Chronic β-adrenergic activation leads to increased glycogen accumulation in adipocytes expressing UCP1. Adipocyte-specific deletion of a scaffolding protein, protein targeting to glycogen (PTG), reduces glycogen levels in beige adipocytes, attenuating UCP1 expression and responsiveness to cold or β-adrenergic receptor-stimulated weight loss in obese mice. Unexpectedly, we observed that glycogen synthesis and degradation are increased in response to catecholamines, and that glycogen turnover is required to produce reactive oxygen species leading to the activation of p38 MAPK, which drives UCP1 expression. Thus, glycogen has a key regulatory role in adipocytes, linking glucose metabolism to thermogenesis.
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http://dx.doi.org/10.1038/s41586-021-04019-8DOI Listing
November 2021

Sex-specific genetic regulation of adipose mitochondria and metabolic syndrome by Ndufv2.

Nat Metab 2021 Nov 25;3(11):1552-1568. Epub 2021 Oct 25.

Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA.

We have previously suggested a central role for mitochondria in the observed sex differences in metabolic traits. However, the mechanisms by which sex differences affect adipose mitochondrial function and metabolic syndrome are unclear. Here we show that in both mice and humans, adipose mitochondrial functions are elevated in females and are strongly associated with adiposity, insulin resistance and plasma lipids. Using a panel of diverse inbred strains of mice, we identify a genetic locus on mouse chromosome 17 that controls mitochondrial mass and function in adipose tissue in a sex- and tissue-specific manner. This locus contains Ndufv2 and regulates the expression of at least 89 mitochondrial genes in females, including oxidative phosphorylation genes and those related to mitochondrial DNA content. Overexpression studies indicate that Ndufv2 mediates these effects by regulating supercomplex assembly and elevating mitochondrial reactive oxygen species production, which generates a signal that increases mitochondrial biogenesis.
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http://dx.doi.org/10.1038/s42255-021-00481-wDOI Listing
November 2021

Gene-Environment Interactions for Cardiovascular Disease.

Curr Atheroscler Rep 2021 10 14;23(12):75. Epub 2021 Oct 14.

Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 2250 Alcazar Street, CSC202, Los Angeles, CA, 90033, USA.

Purpose Of Review: We provide an overview of recent findings with respect to gene-environment (GxE) interactions for cardiovascular disease (CVD) risk and discuss future opportunities for advancing the field.

Recent Findings: Over the last several years, GxE interactions for CVD have mostly been identified for smoking and coronary artery disease (CAD) or related risk factors. By comparison, there is more limited evidence for GxE interactions between CVD outcomes and other exposures, such as physical activity, air pollution, diet, and sex. The establishment of large consortia and population-based cohorts, in combination with new computational tools and mouse genetics platforms, can potentially overcome some of the limitations that have hindered human GxE interaction studies and reveal additional association signals for CVD-related traits. The identification of novel GxE interactions is likely to provide a better understanding of the pathogenesis and genetic liability of CVD, with significant implications for healthy lifestyles and therapeutic strategies.
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http://dx.doi.org/10.1007/s11883-021-00974-9DOI Listing
October 2021

Serum lipids are associated with nonalcoholic fatty liver disease: a pilot case-control study in Mexico.

Lipids Health Dis 2021 Oct 10;20(1):136. Epub 2021 Oct 10.

UCLA Lipidomics Laboratory, David Geffen School of Medicine, Los Angeles, CA, USA.

Background: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and cirrhosis. NAFLD is mediated by changes in lipid metabolism and known risk factors include obesity, metabolic syndrome, and diabetes. The aim of this study was to better understand differences in the lipid composition of individuals with NAFLD compared to controls, by performing direct infusion lipidomics on serum biospecimens from a cohort study of adults in Mexico.

Methods: A nested case-control study was conducted with a sample of 98 NAFLD cases and 100 healthy controls who are participating in an on-going, longitudinal study in Mexico. NAFLD cases were clinically confirmed using elevated liver enzyme tests and liver ultrasound or liver ultrasound elastography, after excluding alcohol abuse, and 100 controls were identified as having at least two consecutive normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (< 40 U/L) results in a 6-month period, and a normal liver ultrasound elastography result in January 2018. Samples were analyzed on the Sciex Lipidyzer Platform and quantified with normalization to serum volume. As many as 1100 lipid species can be identified using the Lipidyzer targeted multiple-reaction monitoring list. The association between serum lipids and NAFLD was investigated using analysis of covariance, random forest analysis, and by generating receiver operator characteristic (ROC) curves.

Results: NAFLD cases had differences in total amounts of serum cholesterol esters, lysophosphatidylcholines, sphingomyelins, and triacylglycerols (TAGs), however, other lipid subclasses were similar to controls. Analysis of individual TAG species revealed increased incorporation of saturated fatty acyl tails in serum of NAFLD cases. After adjusting for age, sex, body mass index, and PNPLA3 genotype, a combined panel of ten lipids predicted case or control status better than an area under the ROC curve of 0.83.

Conclusions: These preliminary results indicate that the serum lipidome differs in patients with NAFLD, compared to healthy controls, and suggest that assessing the desaturation state of TAGs or a specific lipid panel may be useful clinical tools for the diagnosis of NAFLD.
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http://dx.doi.org/10.1186/s12944-021-01526-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504048PMC
October 2021

Pcpe2, a Novel Extracellular Matrix Protein, Regulates Adipocyte SR-BI-Mediated High-Density Lipoprotein Uptake.

Arterioscler Thromb Vasc Biol 2021 11 23;41(11):2708-2725. Epub 2021 Sep 23.

Department of Medicine, Division of Endocrinology and Molecular Medicine (H.X., S.K., A.B.O., E.M., B.G., D.S., M.G.S.-T.), Medical College of Wisconsin, Milwaukee.

Objective: To investigate the role of adipocyte Pcpe2 (procollagen C-endopeptidase enhancer 2) in SR-BI (scavenger receptor class BI)-mediated HDL-C (high-density lipoprotein cholesterol) uptake and contributions to adipose lipid storage.

Approach And Results: Pcpe2, a glycoprotein devoid of intrinsic proteolytic activity, is believed to participate in extracellular protein-protein interactions, supporting SR-BI- mediated HDL-C uptake. In published studies, Pcpe2 deficiency increased the development of atherosclerosis by reducing SR-BI-mediated HDL-C catabolism, but the biological impact of this deficiency on adipocyte SR-BI-mediated HDL-C uptake is unknown. Differentiated cells from Ldlr-/-/Pcpe2-/- (Pcpe2-/-) mouse adipose tissue showed elevated SR-BI protein levels, but significantly reduced HDL-C uptake compared to Ldlr-/- (control) adipose tissue. SR-BI-mediated HDL-C uptake was restored by preincubation of cells with exogenous Pcpe2. In diet-fed mice lacking Pcpe2, significant reductions in visceral, subcutaneous, and brown adipose tissue mass were observed, despite elevations in plasma triglyceride and cholesterol concentrations. Significant positive correlations exist between adipose mass and Pcpe2 expression in both mice and humans.

Conclusions: Overall, these findings reveal a novel and unexpected function for Pcpe2 in modulating SR-BI expression and function as it relates to adipose tissue expansion and cholesterol balance in both mice and humans.
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http://dx.doi.org/10.1161/ATVBAHA.121.316615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551036PMC
November 2021

Dietary and Pharmacologic Manipulations of Host Lipids and Their Interaction With the Gut Microbiome in Non-human Primates.

Front Med (Lausanne) 2021 26;8:646710. Epub 2021 Aug 26.

Departments of Medicine, Microbiology and Human Genetics, University of California, Los Angeles, Los Angeles, CA, United States.

The gut microbiome influences nutrient processing as well as host physiology. Plasma lipid levels have been associated with the microbiome, although the underlying mechanisms are largely unknown, and the effects of dietary lipids on the gut microbiome in humans are not well-studied. We used a compilation of four studies utilizing non-human primates ( and ) with treatments that manipulated plasma lipid levels using dietary and pharmacological techniques, and characterized the microbiome using 16S rDNA. High-fat diets significantly reduced alpha diversity (Shannon) and the Firmicutes/Bacteroidetes ratio compared to chow diets, even when the diets had different compositions and were applied in different orders. When analyzed for differential abundance using DESeq2, , and were greater in both chow diets while , and were greater in both high-fat diets (oleic blend or lard fat source). Dietary cholesterol levels did not affect the microbiome and neither did alterations of plasma lipid levels through treatments of miR-33 antisense oligonucleotide (anti-miR-33), Niemann-Pick C1-Like 1 (NPC1L1) antisense oligonucleotide (ASO), and inducible degrader of LDLR (IDOL) ASO. However, a liver X receptor (LXR) agonist shifted the microbiome and decreased bile acid levels. Fifteen genera increased with the LXR agonist, while seven genera decreased. increased on the LXR agonist and was negatively correlated to deoxycholic acid, cholic acid, and total bile acids while was positively correlated with taurolithocholic acid and taurodeoxycholic acid. Seven of the nine bile acids identified in the feces significantly decreased due to the LXR agonist, and total bile acids (nmol/g) was reduced by 62%. These results indicate that plasma lipid levels have, at most, a modest effect on the microbiome, whereas bile acids, derived in part from plasma lipids, are likely responsible for the indirect relationship between lipid levels and the microbiome.
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http://dx.doi.org/10.3389/fmed.2021.646710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426918PMC
August 2021

Oxy210, a novel inhibitor of hedgehog and TGF-β signalling, ameliorates hepatic fibrosis and hypercholesterolemia in mice.

Endocrinol Diabetes Metab 2021 Oct 31;4(4):e00296. Epub 2021 Aug 31.

Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

Aims: Non-alcoholic steatohepatitis (NASH) is associated with increased overall morbidity and mortality in non-alcoholic fatty liver disease (NAFLD) patients. Liver fibrosis is the strongest prognostic factor for clinical outcomes, liver-related mortality and liver transplantation. Currently, no single therapy or medication for NASH has been approved by the U.S. Food and Drug Administration (FDA). Oxy210, an oxysterol derivative, displays the unique property of antagonizing both Hedgehog (Hh) and transforming growth factor-beta (TGF-β) signalling in primary human hepatic stellate cells (HSC). We hypothesized that inhibition of both Hh and TGF-β signalling by Oxy210 could reduce hepatic fibrosis in NASH. In this study, we examined the therapeutic potential of Oxy210 on NASH in vivo.

Methods: We examined the effect of Oxy210 treatment on Hh and TGF-β pathways in HSC. The efficacy of Oxy210 on liver fibrosis was tested in a 'humanized' hyperlipidemic mouse model of NASH that has high relevance to human pathology.

Approach And Results: We show that Oxy210 inhibits both Hh and TGF-β pathways in human HSC and attenuates baseline and TGF-β-induced expression of pro-fibrotic genes in vitro. Oral delivery of Oxy210 in food resulted in significant liver exposure and significantly reduced hepatic fibrosis in mice over the course of the 16-week study with no apparent safety issues. Additionally, we observed several benefits related to NASH phenotype: (a) reduced plasma pro-inflammatory cytokine and the corresponding hepatic gene expression; (b) reduced pro-fibrotic cytokine and inflammasome gene expression in the liver; (c) reduced apoptosis in the liver; (d) reduced hepatic unesterified cholesterol accumulation; and (e) reduced plasma total and unesterified cholesterol levels.

Conclusions: Oxy210 effectively ameliorated hepatic fibrosis and inflammation and improved hypercholesterolemia in mice. Our findings suggest that Oxy210 and related analogues are a new class of drug candidates that may serve as potential therapeutics candidates for NASH.
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http://dx.doi.org/10.1002/edm2.296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502222PMC
October 2021

NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice.

Sci Rep 2021 08 12;11(1):16409. Epub 2021 Aug 12.

Department of Microbiology, Immunology, and Molecular Genetics, Division of Cardiology, Department of Medicine, Department of Human Genetics, University of California, 10833 Le Conte Avenue, A2-237 CHS, Los Angeles, CA, 90095-1679, USA.

We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose. We now report studies of chronic overexpression of NOTUM in liver indicating that it protects against diet-induced obesity and improves glucose homeostasis in mice. Adeno-associated virus (AAV) vectors were used to overexpress GFP or mouse Notum in the livers of male C57BL/6J mice and the mice were fed an obesifying diet. After 14 weeks of high fat, high sucrose diet feeding, the AAV-Notum mice exhibited decreased obesity and improved glucose tolerance compared to the AAV-GFP mice. Gene expression and immunoblotting analysis of the inguinal fat and brown fat revealed increased expression of beige/brown adipocyte markers in the AAV-Notum group, suggesting enhanced thermogenic capacity by NOTUM. A β3 adrenergic receptor agonist-stimulated lipolysis test suggested increased lipolysis capacity by NOTUM. The levels of collagen and C-C motif chemokine ligand 2 (CCL2) in the epididymal white adipose tissue of the AAV-Notum mice were significantly reduced, suggesting decreased fibrosis and inflammation, respectively. RNA sequencing analysis of inguinal white adipose of 4-week chow diet-fed mice revealed a highly significant enrichment of extracellular matrix (ECM) functional cluster among the down-regulated genes in the AAV-Notum group, suggesting a potential mechanism contributing to improved glucose homeostasis. Our in vitro studies demonstrated that recombinant human NOTUM protein blocked the inhibitory effects of WNT3A on brown adipocyte differentiation. Furthermore, NOTUM attenuated WNT3A's effects on upregulation of TGF-β signaling and its downstream targets. Overall, our data suggest that NOTUM modulates adipose tissue function by promoting thermogenic capacity and inhibiting fibrosis through inhibition of Wnt signaling.
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http://dx.doi.org/10.1038/s41598-021-95720-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361163PMC
August 2021

Genome-Wide Association Study Identifies a Functional Variant Associated With HDL-C (High-Density Lipoprotein Cholesterol) Levels and Premature Coronary Artery Disease.

Arterioscler Thromb Vasc Biol 2021 09 8;41(9):2494-2508. Epub 2021 Jul 8.

Baker Heart and Diabetes Institute, Melbourne, VIC, Australia (A.C.C., B.G.D.).

Objective: Low HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population.

Approach And Results: A genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP, ABCA1, LIPC, and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts (P=5.9×10−18 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism.

Conclusions: This is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.
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http://dx.doi.org/10.1161/ATVBAHA.120.315391DOI Listing
September 2021

ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity.

Sci Transl Med 2021 05;13(594)

Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA.

Although the role of hydrophilic antioxidants in the development of hepatic insulin resistance and nonalcoholic fatty liver disease has been well studied, the role of lipophilic antioxidants remains poorly characterized. A known lipophilic hydrogen peroxide scavenger is bilirubin, which can be oxidized to biliverdin and then reduced back to bilirubin by cytosolic biliverdin reductase. Oxidation of bilirubin to biliverdin inside mitochondria must be followed by the export of biliverdin to the cytosol, where biliverdin is reduced back to bilirubin. Thus, the putative mitochondrial exporter of biliverdin is expected to be a major determinant of bilirubin regeneration and intracellular hydrogen peroxide scavenging. Here, we identified ABCB10 as a mitochondrial biliverdin exporter. ABCB10 reconstituted into liposomes transported biliverdin, and ABCB10 deletion caused accumulation of biliverdin inside mitochondria. Obesity with insulin resistance up-regulated hepatic ABCB10 expression in mice and elevated cytosolic and mitochondrial bilirubin content in an ABCB10-dependent manner. Revealing a maladaptive role of ABCB10-driven bilirubin synthesis, hepatic ABCB10 deletion protected diet-induced obese mice from steatosis and hyperglycemia, improving insulin-mediated suppression of glucose production and decreasing lipogenic SREBP-1c expression. Protection was concurrent with enhanced mitochondrial function and increased inactivation of PTP1B, a phosphatase disrupting insulin signaling and elevating SREBP-1c expression. Restoration of cellular bilirubin content in ABCB10 KO hepatocytes reversed the improvements in mitochondrial function and PTP1B inactivation, demonstrating that bilirubin was the maladaptive effector linked to ABCB10 function. Thus, we identified a fundamental transport process that amplifies intracellular bilirubin redox actions, which can exacerbate insulin resistance and steatosis in obesity.
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http://dx.doi.org/10.1126/scitranslmed.abd1869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300486PMC
May 2021

Sexually Dimorphic Relationships Among Saa3 (Serum Amyloid A3), Inflammation, and Cholesterol Metabolism Modulate Atherosclerosis in Mice.

Arterioscler Thromb Vasc Biol 2021 06 25;41(6):e299-e313. Epub 2021 Mar 25.

Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (A.C., S.W., L.G., D.G., K.E.T., J.T., C.S., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.121.316066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159856PMC
June 2021

Association of serum HDL-cholesterol and apolipoprotein A1 levels with risk of severe SARS-CoV-2 infection.

J Lipid Res 2021 Mar 2;62:100061. Epub 2021 Mar 2.

Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA; Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address:

Individuals with features of metabolic syndrome are particularly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus associated with the severe respiratory disease, coronavirus disease 2019 (COVID-19). Despite considerable attention dedicated to COVID-19, the link between metabolic syndrome and SARS-CoV-2 infection remains unclear. Using data from the UK Biobank, we investigated the relationship between severity of COVID-19 and metabolic syndrome-related serum biomarkers measured prior to SARS-CoV-2 infection. Logistic regression analyses were used to test biomarker levels and biomarker-associated genetic variants with SARS-CoV-2-related outcomes. Among SARS-CoV-2-positive cases and negative controls, a 10 mg/dl increase in serum HDL-cholesterol or apolipoprotein A1 levels was associated with ∼10% reduced risk of SARS-CoV-2 infection, after adjustment for age, sex, obesity, hypertension, type 2 diabetes, and coronary artery disease. Evaluation of known genetic variants for HDL-cholesterol revealed that individuals homozygous for apolipoprotein E4 alleles had ∼2- to 3-fold higher risk of SARS-CoV-2 infection or mortality from COVID-19 compared with apolipoprotein E3 homozygotes, even after adjustment for HDL-cholesterol levels. However, cumulative effects of all evaluated HDL-cholesterol-raising alleles and Mendelian randomization analyses did not reveal association of genetically higher HDL-cholesterol levels with decreased risk of SARS-CoV-2 infection. These results implicate serum HDL-cholesterol and apolipoprotein A1 levels measured prior to SAR-CoV-2 exposure as clinical risk factors for severe COVID-19 infection but do not provide evidence that genetically elevated HDL-cholesterol levels are associated with SAR-CoV-2 infection.
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http://dx.doi.org/10.1016/j.jlr.2021.100061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923911PMC
March 2021

A vicious cycle in atherosclerosis.

Authors:
Aldons J Lusis

Cell 2021 03;184(5):1139-1141

Departments of Medicine, Microbiology and Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Clonal hematopoiesis, defined as the presence of expanded somatic blood cell clones, is associated with about a doubling in the risk of coronary heart disease in humans. Heyde and colleagues now provide evidence that clonal hematopoiesis results largely from increased stem cell proliferation, which is, in turn, stimulated by atherosclerosis.
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http://dx.doi.org/10.1016/j.cell.2021.02.005DOI Listing
March 2021

Loop Diuretics Inhibit Renal Excretion of Trimethylamine -Oxide.

JACC Basic Transl Sci 2021 Feb 27;6(2):103-115. Epub 2021 Jan 27.

Center for Microbiome and Human Health, Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

This study demonstrates, for the first time, that renal tubular excretion of trimethylamine -oxide (TMAO) is inhibited by concomitant loop diuretic administration. The observed marked accumulation in the renal parenchyma, and to lesser extent, plasma, implies differential distributions of TMAO across various tissues and/or systems as a consequence of efflux channel control. A better understanding of TMAO renal clearance and its potential interactions with current and future therapies in patients with heart failure are warranted.
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http://dx.doi.org/10.1016/j.jacbts.2020.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907536PMC
February 2021

Transcription Factor MAFF (MAF Basic Leucine Zipper Transcription Factor F) Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism.

Circulation 2021 05 25;143(18):1809-1823. Epub 2021 Feb 25.

Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany (M.v.S., S.P., H.S.).

Background: Coronary artery disease (CAD) is a multifactorial condition with both genetic and exogenous causes. The contribution of tissue-specific functional networks to the development of atherosclerosis remains largely unclear. The aim of this study was to identify and characterize central regulators and networks leading to atherosclerosis.

Methods: Based on several hundred genes known to affect atherosclerosis risk in mouse (as demonstrated in knockout models) and human (as shown by genome-wide association studies), liver gene regulatory networks were modeled. The hierarchical order and regulatory directions of genes within the network were based on Bayesian prediction models, as well as experimental studies including chromatin immunoprecipitation DNA-sequencing, chromatin immunoprecipitation mass spectrometry, overexpression, small interfering RNA knockdown in mouse and human liver cells, and knockout mouse experiments. Bioinformatics and correlation analyses were used to clarify associations between central genes and CAD phenotypes in both human and mouse.

Results: The transcription factor MAFF (MAF basic leucine zipper transcription factor F) interacted as a key driver of a liver network with 3 human genes at CAD genome-wide association studies loci and 11 atherosclerotic murine genes. Most importantly, expression levels of the low-density lipoprotein receptor (LDLR) gene correlated with MAFF in 600 CAD patients undergoing bypass surgery (STARNET [Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task]) and a hybrid mouse diversity panel involving 105 different inbred mouse strains. Molecular mechanisms of MAFF were tested in noninflammatory conditions and showed positive correlation between MAFF and LDLR in vitro and in vivo. Interestingly, after lipopolysaccharide stimulation (inflammatory conditions), an inverse correlation between MAFF and LDLR in vitro and in vivo was observed. Chromatin immunoprecipitation mass spectrometry revealed that the human CAD genome-wide association studies candidate BACH1 (BTB domain and CNC homolog 1) assists MAFF in the presence of lipopolysaccharide stimulation with respective heterodimers binding at the MAF recognition element of the LDLR promoter to transcriptionally downregulate LDLR expression.

Conclusions: The transcription factor was identified as a novel central regulator of an atherosclerosis/CAD-relevant liver network. triggered context-specific expression of and other genes known to affect CAD risk. Our results suggest that is a missing link between inflammation, lipid and lipoprotein metabolism, and a possible treatment target.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124091PMC
May 2021

Integrative analysis of liver-specific non-coding regulatory SNPs associated with the risk of coronary artery disease.

Am J Hum Genet 2021 03 23;108(3):411-430. Epub 2021 Feb 23.

A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland. Electronic address:

Genetic factors underlying coronary artery disease (CAD) have been widely studied using genome-wide association studies (GWASs). However, the functional understanding of the CAD loci has been limited by the fact that a majority of GWAS variants are located within non-coding regions with no functional role. High cholesterol and dysregulation of the liver metabolism such as non-alcoholic fatty liver disease confer an increased risk of CAD. Here, we studied the function of non-coding single-nucleotide polymorphisms in CAD GWAS loci located within liver-specific enhancer elements by identifying their potential target genes using liver cis-eQTL analysis and promoter Capture Hi-C in HepG2 cells. Altogether, 734 target genes were identified of which 121 exhibited correlations to liver-related traits. To identify potentially causal regulatory SNPs, the allele-specific enhancer activity was analyzed by (1) sequence-based computational predictions, (2) quantification of allele-specific transcription factor binding, and (3) STARR-seq massively parallel reporter assay. Altogether, our analysis identified 1,277 unique SNPs that display allele-specific regulatory activity. Among these, susceptibility enhancers near important cholesterol homeostasis genes (APOB, APOC1, APOE, and LIPA) were identified, suggesting that altered gene regulatory activity could represent another way by which genetic variation regulates serum lipoprotein levels. Using CRISPR-based perturbation, we demonstrate how the deletion/activation of a single enhancer leads to changes in the expression of many target genes located in a shared chromatin interaction domain. Our integrative genomics approach represents a comprehensive effort in identifying putative causal regulatory regions and target genes that could predispose to clinical manifestation of CAD by affecting liver function.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008493PMC
March 2021

Machine Learning Reveals Time-Varying Microbial Predictors with Complex Effects on Glucose Regulation.

mSystems 2021 Feb 16;6(1). Epub 2021 Feb 16.

Institute of Genomics, Estonian Genome Centre, University of Tartu, Tartu, Estonia

The incidence of type 2 diabetes (T2D) has been increasing globally, and a growing body of evidence links type 2 diabetes with altered microbiota composition. Type 2 diabetes is preceded by a long prediabetic state characterized by changes in various metabolic parameters. We tested whether the gut microbiome could have predictive potential for T2D development during the healthy and prediabetic disease stages. We used prospective data of 608 well-phenotyped Finnish men collected from the population-based Metabolic Syndrome in Men (METSIM) study to build machine learning models for predicting continuous glucose and insulin measures in a shorter (1.5 year) and longer (4 year) period. Our results show that the inclusion of the gut microbiome improves prediction accuracy for modeling T2D-associated parameters such as glycosylated hemoglobin and insulin measures. We identified novel microbial biomarkers and described their effects on the predictions using interpretable machine learning techniques, which revealed complex linear and nonlinear associations. Additionally, the modeling strategy carried out allowed us to compare the stability of model performance and biomarker selection, also revealing differences in short-term and long-term predictions. The identified microbiome biomarkers provide a predictive measure for various metabolic traits related to T2D, thus providing an additional parameter for personal risk assessment. Our work also highlights the need for robust modeling strategies and the value of interpretable machine learning. Recent studies have shown a clear link between gut microbiota and type 2 diabetes. However, current results are based on cross-sectional studies that aim to determine the microbial dysbiosis when the disease is already prevalent. In order to consider the microbiome as a factor in disease risk assessment, prospective studies are needed. Our study is the first study that assesses the gut microbiome as a predictive measure for several type 2 diabetes-associated parameters in a longitudinal study setting. Our results revealed a number of novel microbial biomarkers that can improve the prediction accuracy for continuous insulin measures and glycosylated hemoglobin levels. These results make the prospect of using the microbiome in personalized medicine promising.
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http://dx.doi.org/10.1128/mSystems.01191-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573957PMC
February 2021

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle.

J Clin Invest 2021 04;131(8)

Diabetes and Metabolism Research Center and.

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals who were insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PLs) that were differentially abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lysophosphatidylcholine/phosphatidylcholine, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.
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http://dx.doi.org/10.1172/JCI135963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262507PMC
April 2021

Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.

Eur Heart J 2021 03;42(9):919-933

Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands.

Aims: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation.

Methods And Results: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro.

Conclusions: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.
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http://dx.doi.org/10.1093/eurheartj/ehaa1040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936531PMC
March 2021

An integrative multiomic network model links lipid metabolism to glucose regulation in coronary artery disease.

Nat Commun 2021 01 22;12(1):547. Epub 2021 Jan 22.

Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Elevated plasma cholesterol and type 2 diabetes (T2D) are associated with coronary artery disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explore the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic, and clinical data, we identify a glucose and lipid determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impact lipid and glucose levels in inverse directions. Experimental inhibition of one of the GLD network master regulators, lanosterol synthase (LSS), in mice confirms the inverse relationships to glucose and lipid levels as predicted by our model and provides mechanistic insights.
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http://dx.doi.org/10.1038/s41467-020-20750-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822923PMC
January 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515199PMC
February 2021

Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice.

Sci Rep 2021 01 12;11(1):518. Epub 2021 Jan 12.

Division of Cardiology, Department of Medicine, University of California, 10833 Le Conte Avenue, A2-237 CHS, Los Angeles, CA, 90095-1679, USA.

Patients with chronic kidney disease (CKD) have elevated circulating levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes and associated with cardiovascular diseases. High circulating levels of TMAO and its dietary precursor, choline, predict increased risk for development of CKD in apparently healthy subjects, and studies in mice fed TMAO or choline suggest that TMAO can contribute to kidney impairment and renal fibrosis. Here we examined the interactions between TMAO, kidney disease, and cardiovascular disease in mouse models. We observed that while female hyperlipidemic apoE KO mice fed a 0.2% adenine diet for 14 weeks developed CKD with elevated plasma levels of TMAO, provision of a non-lethal inhibitor of gut microbial trimethylamine (TMA) production, iodomethylcholine (IMC), significantly reduced multiple markers of renal injury (plasma creatinine, cystatin C, FGF23, and TMAO), reduced histopathologic evidence of fibrosis, and markedly attenuated development of microalbuminuria. In addition, while the adenine-induced CKD model significantly increased heart weight, a surrogate marker for myocardial hypertrophy, this was largely prevented by IMC supplementation. Surprisingly, adenine feeding did not increase atherosclerosis and significantly decreased the expression of inflammatory genes in the aorta compared to the control groups, effects unrelated to TMAO levels. Our data demonstrate that inhibition of TMAO production attenuated CKD development and cardiac hypertrophy in mice, suggesting that TMAO reduction may be a novel strategy in treating CKD and its cardiovascular disease complications.
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http://dx.doi.org/10.1038/s41598-020-80063-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804188PMC
January 2021

Genetic regulation of liver lipids in a mouse model of insulin resistance and hepatic steatosis.

Mol Syst Biol 2021 01;17(1):e9684

Division of Cardiology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.

To elucidate the contributions of specific lipid species to metabolic traits, we integrated global hepatic lipid data with other omics measures and genetic data from a cohort of about 100 diverse inbred strains of mice fed a high-fat/high-sucrose diet for 8 weeks. Association mapping, correlation, structure analyses, and network modeling revealed pathways and genes underlying these interactions. In particular, our studies lead to the identification of Ifi203 and Map2k6 as regulators of hepatic phosphatidylcholine homeostasis and triacylglycerol accumulation, respectively. Our analyses highlight mechanisms for how genetic variation in hepatic lipidome can be linked to physiological and molecular phenotypes, such as microbiota composition.
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http://dx.doi.org/10.15252/msb.20209684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792507PMC
January 2021

Metabolic reprogramming and epigenetic changes of vital organs in SARS-CoV-2-induced systemic toxicity.

JCI Insight 2021 01 25;6(2). Epub 2021 Jan 25.

Division of Cardiology, Department of Medicine, David Geffen School of Medicine.

Extrapulmonary manifestations of COVID-19 are associated with a much higher mortality rate than pulmonary manifestations. However, little is known about the pathogenesis of systemic complications of COVID-19. Here, we create a murine model of SARS-CoV-2-induced severe systemic toxicity and multiorgan involvement by expressing the human ACE2 transgene in multiple tissues via viral delivery, followed by systemic administration of SARS-CoV-2. The animals develop a profound phenotype within 7 days with severe weight loss, morbidity, and failure to thrive. We demonstrate that there is metabolic suppression of oxidative phosphorylation and the tricarboxylic acid (TCA) cycle in multiple organs with neutrophilia, lymphopenia, and splenic atrophy, mirroring human COVID-19 phenotypes. Animals had a significantly lower heart rate, and electron microscopy demonstrated myofibrillar disarray and myocardial edema, a common pathogenic cardiac phenotype in human COVID-19. We performed metabolomic profiling of peripheral blood and identified a panel of TCA cycle metabolites that served as biomarkers of depressed oxidative phosphorylation. Finally, we observed that SARS-CoV-2 induces epigenetic changes of DNA methylation, which affects expression of immune response genes and could, in part, contribute to COVID-19 pathogenesis. Our model suggests that SARS-CoV-2-induced metabolic reprogramming and epigenetic changes in internal organs could contribute to systemic toxicity and lethality in COVID-19.
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http://dx.doi.org/10.1172/jci.insight.145027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934846PMC
January 2021

Expression Associates With Inflammation in Early Atherosclerosis in Humans and Can Be Therapeutically Silenced to Reduce NF-κB Activation and Atherogenesis in Mice.

Circulation 2021 01 23;143(2):163-177. Epub 2020 Nov 23.

University of Ottawa Heart Institute, Canada (D.K., M.-A.N., M.G., Z.L., H.W., J.W.K., R.J., A.M., A.R., P.L., K.J.R.).

Background: Chronic activation of the innate immune system drives inflammation and contributes directly to atherosclerosis. We previously showed that macrophages in the atherogenic plaque undergo RIPK3 (receptor-interacting serine/threonine-protein kinase 3)-MLKL (mixed lineage kinase domain-like protein)-dependent programmed necroptosis in response to sterile ligands such as oxidized low-density lipoprotein and damage-associated molecular patterns and that necroptosis is active in advanced atherosclerotic plaques. Upstream of the RIPK3-MLKL necroptotic machinery lies RIPK1 (receptor-interacting serine/threonine-protein kinase 1), which acts as a master switch that controls whether the cell undergoes NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells)-dependent inflammation, caspase-dependent apoptosis, or necroptosis in response to extracellular stimuli. We therefore set out to investigate the role of RIPK1 in the development of atherosclerosis, which is driven largely by NF-κB-dependent inflammation at early stages. We hypothesize that, unlike RIPK3 and MLKL, RIPK1 primarily drives NF-κB-dependent inflammation in early atherogenic lesions, and knocking down RIPK1 will reduce inflammatory cell activation and protect against the progression of atherosclerosis.

Methods: We examined expression of RIPK1 protein and mRNA in both human and mouse atherosclerotic lesions, and used loss-of-function approaches in vitro in macrophages and endothelial cells to measure inflammatory responses. We administered weekly injections of RIPK1 antisense oligonucleotides to mice fed a cholesterol-rich (Western) diet for 8 weeks.

Results: We find that RIPK1 expression is abundant in early-stage atherosclerotic lesions in both humans and mice. Treatment with RIPK1 antisense oligonucleotides led to a reduction in aortic sinus and en face lesion areas (47.2% or 58.8% decrease relative to control, <0.01) and plasma inflammatory cytokines (IL-1α [interleukin 1α], IL-17A [interleukin 17A], <0.05) in comparison with controls. knockdown in macrophages decreased inflammatory genes (NF-κB, TNFα [tumor necrosis factor α], IL-1α) and in vivo lipopolysaccharide- and atherogenic diet-induced NF-κB activation. In endothelial cells, knockdown of prevented NF-κB translocation to the nucleus in response to TNFα, where accordingly there was a reduction in gene expression of , , and monocyte attachment.

Conclusions: We identify RIPK1 as a central driver of inflammation in atherosclerosis by its ability to activate the NF-κB pathway and promote inflammatory cytokine release. Given the high levels of RIPK1 expression in human atherosclerotic lesions, our study suggests RIPK1 as a future therapeutic target to reduce residual inflammation in patients at high risk of coronary artery disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.038379DOI Listing
January 2021

Systems toxicogenomics of prenatal low-dose BPA exposure on liver metabolic pathways, gut microbiota, and metabolic health in mice.

Environ Int 2021 01 19;146:106260. Epub 2020 Nov 19.

Department of Integrative Biology and Physiology, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Molecular Toxicology Interdepartmental Program, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Institute for Quantitative and Computational Biosciences, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Electronic address:

Bisphenol A (BPA) is an industrial plasticizer widely found in consumer products, and exposure to BPA during early development has been associated with the prevalence of various cardiometabolic diseases including obesity, metabolic syndrome, type 2 diabetes, and cardiovascular diseases. To elucidate the molecular perturbations underlying the connection of low-dose prenatal BPA exposure to cardiometabolic diseases, we conducted a multi-dimensional systems biology study assessing the liver transcriptome, gut microbial community, and diverse metabolic phenotypes in both male and female mouse offspring exposed to 5 μg/kg/day BPA during gestation. Prenatal exposure to low-dose BPA not only significantly affected liver genes involved in oxidative phosphorylation, PPAR signaling and fatty acid metabolism, but also affected the gut microbial composition in an age- and sex-dependent manner. Bacteria such as those belonging to the S24-7 and Lachnospiraceae families were correlated with offspring phenotypes, differentially expressed liver metabolic genes such as Acadl and Dgat1, and key drivers identified in our gene network modeling such as Malat1 and Apoa2. This multiomics study provides insight into the relationship between gut bacteria and host liver genes that could contribute to cardiometabolic disease risks upon low-dose BPA exposure.
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http://dx.doi.org/10.1016/j.envint.2020.106260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775895PMC
January 2021

Modeling epistasis in mice and yeast using the proportion of two or more distinct genetic backgrounds: Evidence for "polygenic epistasis".

PLoS Genet 2020 10 26;16(10):e1009165. Epub 2020 Oct 26.

Department of Neurology, UCLA, Los Angeles, CA, United States of America.

Background: The majority of quantitative genetic models used to map complex traits assume that alleles have similar effects across all individuals. Significant evidence suggests, however, that epistatic interactions modulate the impact of many alleles. Nevertheless, identifying epistatic interactions remains computationally and statistically challenging. In this work, we address some of these challenges by developing a statistical test for polygenic epistasis that determines whether the effect of an allele is altered by the global genetic ancestry proportion from distinct progenitors.

Results: We applied our method to data from mice and yeast. For the mice, we observed 49 significant genotype-by-ancestry interaction associations across 14 phenotypes as well as over 1,400 Bonferroni-corrected genotype-by-ancestry interaction associations for mouse gene expression data. For the yeast, we observed 92 significant genotype-by-ancestry interactions across 38 phenotypes. Given this evidence of epistasis, we test for and observe evidence of rapid selection pressure on ancestry specific polymorphisms within one of the cohorts, consistent with epistatic selection.

Conclusions: Unlike our prior work in human populations, we observe widespread evidence of ancestry-modified SNP effects, perhaps reflecting the greater divergence present in crosses using mice and yeast.
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http://dx.doi.org/10.1371/journal.pgen.1009165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644088PMC
October 2020

Local M-CSF (Macrophage Colony-Stimulating Factor) Expression Regulates Macrophage Proliferation and Apoptosis in Atherosclerosis.

Arterioscler Thromb Vasc Biol 2021 01 22;41(1):220-233. Epub 2020 Oct 22.

Department of Microbiology, Immunology, and Molecular Genetics (S.K.S., A.M., Z.F., M.M., C.E., D.S., Z.Z., S.C., R.C.D., T.B.R., A.J.L.), University of California, Los Angeles.

Objective: Previous studies have shown that deficiency of M-CSF (macrophage colony-stimulating factor; or CSF1 [colony stimulating factor 1]) dramatically reduces atherosclerosis in hyperlipidemic mice. We characterize the underlying mechanism and investigate the relevant sources of CSF1 in lesions. Approach and Results: We quantitatively assessed the effects of CSF1 deficiency on macrophage proliferation and apoptosis in atherosclerotic lesions. Staining of aortic lesions with markers of proliferation, Ki-67 and bromodeoxyuridine, revealed around 40% reduction in CSF1 heterozygous (Csf1) as compared with WT (wild type; Csf1) mice. Similarly, staining with a marker of apoptosis, activated caspase-3, revealed a 3-fold increase in apoptotic cells in Csf1 mice. Next, we determined the cellular sources of CSF1 contributing to lesion development. Cell-specific deletions of Csf1 in smooth muscle cells using SM22α-Cre (smooth muscle protein 22-alpha-Cre) reduced lesions by about 40%, and in endothelial cells, deletions with Cdh5-Cre (VE-cadherin-Cre) reduced lesions by about 30%. Macrophage-specific deletion with LysM-Cre (lysozyme M-Cre), on the other hand, did not significantly reduce lesions size. Transplantation of Csf1 null (Csf1) mice bone marrow into Csf1 mice reduced lesions by about 35%, suggesting that CSF1 from hematopoietic cells other than macrophages contributes to atherosclerosis. None of the cell-specific knockouts affected circulating CSF1 levels, and only the smooth muscle cell deletions had any effect on the percentage monocytes in the circulation. Also, Csf1 mice did not exhibit significant differences in Ly6C/Ly6C monocytes as compared with Csf1.

Conclusions: CSF1 contributes to both macrophage proliferation and survival in lesions. Local CSF1 production by smooth muscle cell and endothelial cell rather than circulating CSF1 is the primary driver of macrophage expansion in atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.120.315255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769919PMC
January 2021
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