Publications by authors named "David E Stec"

90 Publications

Bilirubin Nanoparticles Reduce Diet-Induced Hepatic Steatosis, Improve Fat Utilization, and Increase Plasma β-Hydroxybutyrate.

Front Pharmacol 2020 18;11:594574. Epub 2020 Dec 18.

Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS, United States.

The inverse relationship of plasma bilirubin levels with liver fat accumulation has prompted the possibility of bilirubin as a therapeutic for non-alcoholic fatty liver disease. Here, we used diet-induced obese mice with non-alcoholic fatty liver disease treated with pegylated bilirubin (bilirubin nanoparticles) or vehicle control to determine the impact on hepatic lipid accumulation. The bilirubin nanoparticles significantly reduced hepatic fat, triglyceride accumulation, lipogenesis, and serum levels of liver dysfunction marker aspartate transaminase and ApoB100 containing very-low-density lipoprotein. The bilirubin nanoparticles improved liver function and activated the hepatic -oxidation pathway by increasing PPARα and acyl-coenzyme A oxidase 1. The bilirubin nanoparticles also significantly elevated plasma levels of the ketone -hydroxybutyrate and lowered liver fat accumulation. This study demonstrates that bilirubin nanoparticles induce hepatic fat utilization, raise plasma ketones, and reduce hepatic steatosis, opening new therapeutic avenues for NAFLD.
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http://dx.doi.org/10.3389/fphar.2020.594574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775678PMC
December 2020

Natural Product Heme Oxygenase Inducers as Treatment for Nonalcoholic Fatty Liver Disease.

Int J Mol Sci 2020 Dec 14;21(24). Epub 2020 Dec 14.

Department of Pharmacology and Nutritional Sciences, University of Kentucky, 760 Press Avenue, Healthy Kentucky Research Building, Lexington, KY 40508, USA.

Heme oxygenase (HO) is a critical component of the defense mechanism to a wide variety of cellular stressors. HO induction affords cellular protection through the breakdown of toxic heme into metabolites, helping preserve cellular integrity. Nonalcoholic fatty liver disease (NAFLD) is a pathological condition by which the liver accumulates fat. The incidence of NAFLD has reached all-time high levels driven primarily by the obesity epidemic. NALFD can progress to nonalcoholic steatohepatitis (NASH), advancing further to liver cirrhosis or cancer. NAFLD is also a contributing factor to cardiovascular and metabolic diseases. There are currently no drugs to specifically treat NAFLD, with most treatments focused on lifestyle modifications. One emerging area for NAFLD treatment is the use of dietary supplements such as curcumin, pomegranate seed oil, milk thistle oil, cold-pressed oil, and resveratrol, among others. Recent studies have demonstrated that several of these natural dietary supplements attenuate hepatic lipid accumulation and fibrosis in NAFLD animal models. The beneficial actions of several of these compounds are associated with the induction of heme oxygenase-1 (HO-1). Thus, targeting HO-1 through dietary-supplements may be a useful therapeutic for NAFLD either alone or with lifestyle modifications.
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http://dx.doi.org/10.3390/ijms21249493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764878PMC
December 2020

Increased Sirt1 secreted from visceral white adipose tissue is associated with improved glucose tolerance in obese Nrf2-deficient mice.

Redox Biol 2021 01 24;38:101805. Epub 2020 Nov 24.

University Paris-Est Créteil, INSERM, IMRB, F-94010, Créteil, France. Electronic address:

Obesity is associated with metabolic dysregulation characterized by insulin resistance and glucose intolerance. Nuclear factor E2-related factor (Nrf2) is a critical regulator of the stress response and Nrf2-deficient mice (Nrf2) are protected against high fat diet (HFD)-induced metabolic derangement. We searched for factors that could underline this favorable phenotype and found that Nrf2 mice exhibit higher circulating levels of sirtuin 1 (Sirt1), a key player in cellular homeostasis and energy metabolism, compared to wild-type mice. Increased Sirt1 levels in Nrf2 mice were found not only in animals under standard diet but also following HFD. Interestingly, we report here that the visceral adipose tissue (eWAT) is the sole source of increased Sirt1 protein in plasma. eWAT and other fat depots displayed enhanced adipocytes lipolysis, increased fatty acid oxidation and glycolysis, suggesting autocrine and endocrine actions of Sirt1 in this model. We further demonstrate that removal of eWAT completely abolishes the increase in circulating Sirt1 and that this procedure suppresses the beneficial effect of Nrf2 deficiency on glucose tolerance, but not insulin sensitivity, following a HFD regime. Thus, in contrast to many other stressful conditions where Nrf2 deficiency exacerbates damage, our study indicates that up-regulation of Sirt1 levels specifically in the visceral adipose tissue of Nrf2 mice is a key adaptive mechanism that mitigates glucose intolerance induced by nutritional stress.
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http://dx.doi.org/10.1016/j.redox.2020.101805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721645PMC
January 2021

Bilirubin as a metabolic hormone: the physiological relevance of low levels.

Am J Physiol Endocrinol Metab 2021 02 7;320(2):E191-E207. Epub 2020 Dec 7.

Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky.

Recent research on bilirubin, a historically well-known waste product of heme catabolism, suggests an entirely new function as a metabolic hormone that drives gene transcription by nuclear receptors. Studies are now revealing that low plasma bilirubin levels, defined as "hypobilirubinemia," are a possible new pathology analogous to the other end of the spectrum of extreme hyperbilirubinemia seen in patients with jaundice and liver dysfunction. Hypobilirubinemia is most commonly seen in patients with metabolic dysfunction, which may lead to cardiovascular complications and possibly stroke. We address the clinical significance of low bilirubin levels. A better understanding of bilirubin's hormonal function may explain why hypobilirubinemia might be deleterious. We present mechanisms by which bilirubin may be protective at mildly elevated levels and research directions that could generate treatment possibilities for patients with hypobilirubinemia, such as targeting of pathways that regulate its production or turnover or the newly designed bilirubin nanoparticles. Our review here calls for a shift in the perspective of an old molecule that could benefit millions of patients with hypobilirubinemia.
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http://dx.doi.org/10.1152/ajpendo.00405.2020DOI Listing
February 2021

Milk thistle seed cold press oil attenuates markers of the metabolic syndrome in a mouse model of dietary-induced obesity.

J Food Biochem 2020 12 12;44(12):e13522. Epub 2020 Oct 12.

Department of Medicine, New York Medical College, Valhalla, NY, USA.

Milk thistle cold press oil (MTO) is an herbal remedy derived from Silybum marianum which contains a low level of silymarin and mixture of polyphenols and flavonoids. The effect of MTO on the cardiovascular and metabolic complications of obesity was studied in mice that were fed a high-fat diet (HFD) for 20 weeks and treated with MTO for the final 8 weeks of the diet. MTO treatment attenuated HFD-induced obesity, fasting hyperglycemia, hypertension, and induced markers of mitochondrial fusion and browning of white adipose. Markers of inflammation were also attenuated in both adipose and the liver of MTO-treated mice. In addition, MTO resulted in the improvement of liver fibrosis. These results demonstrate that MTO has beneficial actions to attenuate dietary obesity-induced weight gain, hyperglycemia, hypertension, inflammation, and suggest that MTO supplementation may prove beneficial to patients exhibiting symptoms of metabolic syndrome. PRACTICAL APPLICATIONS: Natural supplements are increasingly being considered as potential therapies for many chronic cardiovascular and metabolic diseases. Milk thistle cold press oil (MTO) is derived from Silybum marianum which is used as a dietary supplement in different parts of the world. The results of the present study demonstrate that MTO supplementation normalizes several metabolic and cardiovascular complications arising from dietary-induced obesity. MTO supplementation also had anti-inflammatory actions in the adipose as well as the liver. These results suggest that supplementation of MTO into the diet of obese individuals may afford protection against the worsening of cardiovascular and metabolic disease and improve inflammation and liver fibrosis.
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http://dx.doi.org/10.1111/jfbc.13522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770619PMC
December 2020

Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1.

Antioxidants (Basel) 2020 Sep 19;9(9). Epub 2020 Sep 19.

Center for Excellence in Cardiovascular-Renal Research, Department of Physiology & Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 392161, USA.

Exercise in humans and animals increases plasma bilirubin levels, but the mechanism by which this occurs is unknown. In the present study, we utilized rats genetically selected for high capacity running (HCR) and low capacity running (LCR) to determine pathways in the liver that aerobic exercise modifies to control plasma bilirubin. The HCR rats, compared to the LCR, exhibited significantly higher levels of plasma bilirubin and the hepatic enzyme that produces it, biliverdin reductase-A (BVRA). The HCR also had reduced expression of the glucuronyl hepatic enzyme UGT1A1, which lowers plasma bilirubin. Recently, bilirubin has been shown to activate the peroxisome proliferator-activated receptor-α (PPARα), a ligand-induced transcription factor, and the higher bilirubin HCR rats had significantly increased PPARα-target genes , , and . These are known to promote liver function and glycogen storage, which we found by Periodic acid-Schiff (PAS) staining that hepatic glycogen content was higher in the HCR versus the LCR. Our results demonstrate that exercise stimulates pathways that raise plasma bilirubin through alterations in hepatic enzymes involved in bilirubin synthesis and metabolism, improving liver function, and glycogen content. These mechanisms may explain the beneficial effects of exercise on plasma bilirubin levels and health in humans.
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http://dx.doi.org/10.3390/antiox9090889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554716PMC
September 2020

Cold Press Pomegranate Seed Oil Attenuates Dietary-Obesity Induced Hepatic Steatosis and Fibrosis through Antioxidant and Mitochondrial Pathways in Obese Mice.

Int J Mol Sci 2020 Jul 31;21(15). Epub 2020 Jul 31.

Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA.

Aim: Obesity is associated with metabolic syndrome, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. In this study, we investigated whether the dietary supplementation of pomegranate seed oil (PSO) exerted a protective effect on liver lipid uptake, fibrosis, and mitochondrial function in a mouse model of obesity and insulin resistance.

Method: In this in vivo study, eight-week-old C57BL/6J male mice were fed with a high fat diet (HFD) for 24 weeks and then were divided into three groups as follows: group (1) Lean; group ( = 6) (2) HF diet; group ( = 6) (3) HF diet treated with PSO (40 mL/kg food) ( = 6) for eight additional weeks starting at 24 weeks. Physiological parameters, lipid droplet accumulation, inflammatory biomarkers, antioxidant biomarkers, mitochondrial biogenesis, insulin sensitivity, and hepatic fibrosis were determined to examine whether PSO intervention prevents obesity-associated metabolic syndrome.

Results: The PSO group displayed an increase in oxygen consumption, as well as a decrease in fasting glucose and blood pressure ( < 0.05) when compared to the HFD-fed mice group. PSO increased both the activity and expression of hepatic HO-1, downregulated inflammatory adipokines, and decreased hepatic fibrosis. PSO increased the levels of thermogenic genes, mitochondrial signaling, and lipid metabolism through increases in Mfn2, OPA-1, PRDM 16, and PGC1α. Furthermore, PSO upregulated obesity-mediated hepatic insulin receptor phosphorylation Tyr-, p-IRB tyr, and pAMPK, thereby decreasing insulin resistance.

Conclusions: These results indicated that PSO decreased obesity-mediated insulin resistance and the progression of hepatic fibrosis through an improved liver signaling, as manifested by increased insulin receptor phosphorylation and thermogenic genes. Furthermore, our findings indicate a potential therapeutic role for PSO in the prevention of obesity-associated NAFLD, NASH, and other metabolic disorders.
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http://dx.doi.org/10.3390/ijms21155469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432301PMC
July 2020

Cold-Pressed Oil Standardized to 3% Thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation, and Markers of Insulin Resistance Accompanied with Conversion of White to Beige Fat in Mice.

Antioxidants (Basel) 2020 Jun 4;9(6). Epub 2020 Jun 4.

Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.

Excessive lipid accumulation in white adipose tissue (WAT) results in adipocyte hypertrophy and chronic low-grade inflammation, which is the major cause of obesity-associated insulin resistance and consequent metabolic disease. The development of beige adipocytes in WAT (browning of WAT) increases energy expenditure and has been considered as a novel strategy to counteract obesity. Thymoquinone (TQ) is the main bioactive quinone derived from the plant and has antioxidative and anti-inflammatory capacities. Fish oil omega 3 (ω3) enhances both insulin sensitivity and glucose homeostasis in obesity, but the involved mechanisms remain unclear. The aim of this study is to explore the effects of TQ and ω3 PUFAs (polyunsaturated fatty acids) on obesity-associated inflammation, markers of insulin resistance, and the metabolic effects of adipose tissue browning. 3T3-L1 cells were cultured to investigate the effects of TQ and ω3 on the browning of WAT. C57BL/6J mice were fed a high-fat diet (HFD), supplemented with 0.75% TQ, and 2% ω3 in combination for eight weeks. In 3T3-L1 cells, TQ and ω3 reduced lipid droplet size and increased hallmarks of beige adipocytes such as uncoupling protein-1 (UCP1), PR domain containing 16 (PRDM16), fibroblast growth factor 21 (FGF21), Sirtuin 1 (Sirt1), Mitofusion 2 (Mfn2), and heme oxygenase 1 (HO-1) protein expression, as well as increased the phosphorylation of Protein Kinase B (AKT) and insulin receptors. In the adipose tissue of HFD mice, TQ and ω3 treatment attenuated levels of inflammatory adipokines, Nephroblastoma Overexpressed (NOV/CCN3) and Twist related protein 2 (TWIST2), and diminished adipocyte hypoxia by decreasing HIF1α expression and hallmarks of beige adipocytes such as UCP1, PRDM16, FGF21, and mitochondrial biogenesis markers Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), Sirt1, and Mfn2. Increased 5' adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation and HO-1 expression were observed in adipose with TQ and ω3 treatment, which led to increased pAKT and pIRS1 Ser expression. In addition to the adipose, TQ and ω3 also increased inflammation and markers of insulin sensitivity in the liver, as demonstrated by increased phosphorylated insulin receptor (pIR tyr), insulin receptor beta (IRβ), UCP1, and pIRS1 Ser and reduced NOV/CCN3 expression. Our data demonstrate the enhanced browning of WAT from TQ treatment in combination with ω3, which may play an important role in decreasing obesity-associated insulin resistance and in reducing the chronic inflammatory state of obesity.
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http://dx.doi.org/10.3390/antiox9060489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346210PMC
June 2020

Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator-activated receptor α.

J Biol Chem 2020 07 13;295(29):9804-9822. Epub 2020 May 13.

Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA

Activation of lipid-burning pathways in the fat-storing white adipose tissue (WAT) is a promising strategy to improve metabolic health and reduce obesity, insulin resistance, and type II diabetes. For unknown reasons, bilirubin levels are negatively associated with obesity and diabetes. Here, using mice and an array of approaches, including MRI to assess body composition, biochemical assays to measure bilirubin and fatty acids, MitoTracker-based mitochondrial analysis, immunofluorescence, and high-throughput coregulator analysis, we show that bilirubin functions as a molecular switch for the nuclear receptor transcription factor peroxisome proliferator-activated receptor α (PPARα). Bilirubin exerted its effects by recruiting and dissociating specific coregulators in WAT, driving the expression of PPARα target genes such as uncoupling protein 1 () and adrenoreceptor β 3 (). We also found that bilirubin is a selective ligand for PPARα and does not affect the activities of the related proteins PPARγ and PPARδ. We further found that diet-induced obese mice with mild hyperbilirubinemia have reduced WAT size and an increased number of mitochondria, associated with a restructuring of PPARα-binding coregulators. We conclude that bilirubin strongly affects organismal body weight by reshaping the PPARα coregulator profile, remodeling WAT to improve metabolic function, and reducing fat accumulation.
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http://dx.doi.org/10.1074/jbc.RA120.013700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380202PMC
July 2020

Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice.

Biomolecules 2020 03 2;10(3). Epub 2020 Mar 2.

Center for Excellence in Cardiovascular-Renal Research, Department of Physiology & Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 392161, USA.

Biliverdin reductase (BVR) is an enzymatic and signaling protein that has multifaceted roles in physiological systems. Despite the wealth of knowledge about BVR, no data exist regarding its actions in adipocytes. Here, we generated an adipose-specific deletion of biliverdin reductase-A (BVRA) () in mice to determine the function of BVRA in adipocytes and how it may impact adipose tissue expansion. The and littermate control () mice were placed on a high-fat diet (HFD) for 12 weeks. Body weights were measured weekly and body composition, fasting blood glucose and insulin levels were quantitated at the end of the 12 weeks. The data showed that the percent body fat and body weights did not differ between the groups; however, mice had significantly higher visceral fat as compared to the . The loss of adipocyte BVRA decreased the mitochondrial number in white adipose tissue (WAT), and increased inflammation and adipocyte size, but this was not observed in brown adipose tissue (BAT). There were genes significantly reduced in WAT that induce the browning effect such as Ppara and , indicating that BVRA improves mitochondria function and beige-type white adipocytes. The mice also had significantly higher fasting blood glucose levels and no changes in plasma insulin levels, which is indicative of decreased insulin signaling in WAT, as evidenced by reduced levels of phosphorylated AKT (pAKT) and Glut4 mRNA. These results demonstrate the essential role of BVRA in WAT in insulin signaling and adipocyte hypertrophy.
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http://dx.doi.org/10.3390/biom10030387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175174PMC
March 2020

Progress in heme oxygenase research.

Arch Biochem Biophys 2020 05 24;685:108321. Epub 2020 Feb 24.

Department of Physiology and Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MS, USA.

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http://dx.doi.org/10.1016/j.abb.2020.108321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344117PMC
May 2020

Bilirubin Safeguards Cardiorenal and Metabolic Diseases: a Protective Role in Health.

Curr Hypertens Rep 2019 10 10;21(11):87. Epub 2019 Oct 10.

Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS, 39216, USA.

Purpose Of Review: To discuss recent advances indicating that bilirubin safeguards against cardiorenal and metabolic diseases.

Recent Findings: Several investigations from human patient populations and experimental animal models have shown that bilirubin improves cardiorenal and metabolic dysfunction. The latest studies found an entirely new function of bilirubin suggesting that it acts as a hormone signaling molecule capable of activating nuclear receptors for burning fat, which may explain several of its protective actions. This review highlights the current findings (within the last 3 years) regarding cardiorenal and metabolic protective effects of bilirubin and the latest mechanism(s) that may be mediating these effects.
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http://dx.doi.org/10.1007/s11906-019-0994-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938163PMC
October 2019

Loss of hepatic PPARα promotes inflammation and serum hyperlipidemia in diet-induced obesity.

Am J Physiol Regul Integr Comp Physiol 2019 11 4;317(5):R733-R745. Epub 2019 Sep 4.

Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio.

Agonists for PPARα are used clinically to reduce triglycerides and improve high-density lipoprotein (HDL) cholesterol levels in patients with hyperlipidemia. Whether the mechanism of PPARα activation to lower serum lipids occurs in the liver or other tissues is unknown. To determine the function of hepatic PPARα on lipid profiles in diet-induced obese mice, we placed hepatocyte-specific peroxisome proliferator-activated receptor-α (PPARα) knockout () and wild-type () mice on high-fat diet (HFD) or normal fat diet (NFD) for 12 wk. There was no significant difference in weight gain, percent body fat mass, or percent body lean mass between the groups of mice in response to HFD or NFD. Interestingly, the mice on HFD had worsened hepatic inflammation and a significant shift in the proinflammatory M1 macrophage population. These changes were associated with higher hepatic fat mass and decreased hepatic lean mass in the on HFD but not in NFD as measured by Oil Red O and noninvasive EchoMRI analysis (31.1 ± 2.8 vs. 20.2 ± 1.5, 66.6 ± 2.5 vs. 76.4 ± 1.5%, < 0.05). We did find that this was related to significantly reduced peroxisomal gene function and lower plasma β-hydroxybutyrate in the on HFD, indicative of reduced metabolism of fats in the liver. Together, these provoked higher plasma triglyceride and apolipoprotein B100 levels in the mice compared with on HFD. These data indicate that hepatic PPARα functions to control inflammation and liver triglyceride accumulation that prevent hyperlipidemia.
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http://dx.doi.org/10.1152/ajpregu.00153.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879843PMC
November 2019

CRISPR Cas9-mediated deletion of biliverdin reductase A (BVRA) in mouse liver cells induces oxidative stress and lipid accumulation.

Arch Biochem Biophys 2019 09 15;672:108072. Epub 2019 Aug 15.

Department of Physiology & Biophysics, Mississippi Center for Obesity Research, USA. Electronic address:

Obesity is the predominant cause of non-alcoholic fatty liver disease (NAFLD), which is associated with insulin resistance and diabetes. NAFLD includes a spectrum of pathologies that starts with simple steatosis, which can progress to non-alcoholic steatohepatitis (NASH) with the commission of other factors such as the enhancement of reactive oxygen species (ROS). Biliverdin reductase A (BVRA) reduces biliverdin to the antioxidant bilirubin, which may serve to prevent NAFLD, and possibly the progression to NASH. To further understand the role of BVRA in hepatic function, we used CRISPR-Cas9 technology to target the Blvra gene in the murine hepa1c1c7 hepatocyte cell line (BVRA KO). BVRA activity and protein levels were significantly lower in BVRA KO vs. wild-type (WT) hepatocytes. Lipid accumulation under basal and serum-starved conditions was significantly (p < 0.05) higher in BVRA KO vs. WT cells. The loss of BVRA resulted in the reduction of mitochondria number, decreased expression of markers of mitochondrial biogenesis, uncoupling, oxidation, and fusion, which paralleled reduced mitochondrial oxygen consumption. BVRA KO cells exhibited increased levels of ROS generation and decreased levels of superoxide dismutase mRNA expression. In conclusion, our data demonstrate a critical role for BVRA in protecting against lipid accumulation and oxidative stress in hepatocytes, which may serve as a future therapeutic target for NAFLD and its progression to NASH.
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http://dx.doi.org/10.1016/j.abb.2019.108072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718297PMC
September 2019

Targeting Heme Oxygenase-1 in Cardiovascular and Kidney Disease.

Antioxidants (Basel) 2019 Jun 18;8(6). Epub 2019 Jun 18.

Department of Physiology and Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MI 39216, USA.

Heme oxygenase (HO) plays an important role in the cardiovascular system. It is involved in many physiological and pathophysiological processes in all organs of the cardiovascular system. From the regulation of blood pressure and blood flow to the adaptive response to end-organ injury, HO plays a critical role in the ability of the cardiovascular system to respond and adapt to changes in homeostasis. There have been great advances in our understanding of the role of HO in the regulation of blood pressure and target organ injury in the last decade. Results from these studies demonstrate that targeting of the HO system could provide novel therapeutic opportunities for the treatment of several cardiovascular and renal diseases. The goal of this review is to highlight the important role of HO in the regulation of cardiovascular and renal function and protection from disease and to highlight areas in which targeting of the HO system needs to be translated to help benefit patient populations.
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http://dx.doi.org/10.3390/antiox8060181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617021PMC
June 2019

RNA sequencing in human HepG2 hepatocytes reveals PPAR-α mediates transcriptome responsiveness of bilirubin.

Physiol Genomics 2019 06 10;51(6):234-240. Epub 2019 May 10.

Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine , Toledo, Ohio.

Bilirubin is a potent antioxidant that reduces inflammation and the accumulation of fat. There have been reports of gene responses to bilirubin, which was mostly attributed to its antioxidant function. Using RNA sequencing, we found that biliverdin, which is rapidly reduced to bilirubin, induced transcriptome responses in human HepG2 hepatocytes in a peroxisome proliferator-activated receptor (PPAR)-α-dependent fashion (398 genes with >2-fold change; false discovery rate < 0.05). For comparison, a much narrower set of genes demonstrated differential expression when PPAR-α was suppressed via lentiviral shRNA knockdown (23 genes). Gene set enrichment analysis revealed the bilirubin-PPAR-α transcriptome mediates pathways for oxidation-reduction processes, mitochondrial function, response to nutrients, fatty acid oxidation, and lipid homeostasis. Together, these findings suggest that transcriptome responses from the generation of bilirubin are mostly PPAR-α dependent, and its antioxidant function regulates a smaller set of genes.
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http://dx.doi.org/10.1152/physiolgenomics.00028.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620644PMC
June 2019

Changes in urinary metabolome related to body fat involve intermediates of choline processing by gut microbiota.

Heliyon 2019 Apr 11;5(4):e01497. Epub 2019 Apr 11.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.

Countering the obesity pandemic will require better understanding of disease mechanisms and development of new diagnostic methods. Small molecule metabolites excreted in urine can be important biomarkers of disease progression and treatment. However, with multiple pathways involved, it has been challenging to identify key pathway(s) that closely follow disease features such as body fat. We employed a high-fat diet (HFD) mouse model of obesity with the goal of determining changes in urinary metabolite profile related to body fat using proton nuclear magnetic resonance (H NMR). Several urinary metabolites with significantly lower levels in HFD compared to control mice have been identified. Specifically, major changes were found in metabolites from tricarboxylic acid (TCA) cycle, amino acid, nicotinamide, and choline metabolism including 2-hydroxydlutarate, -aconitate, -aconitate, alanine, creatine, trigonelline, dimethylamine, and trimethylamine. However, levels of only two metabolites, namely dimethylamine and trimethylamine, showed significant reverse correlation with total body fat. These metabolites derive from choline processing by gut microbiota and may be prospective biomarkers indicative of accumulation of body fat in obesity.
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http://dx.doi.org/10.1016/j.heliyon.2019.e01497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465582PMC
April 2019

Deletion of Biliverdin Reductase A in Myeloid Cells Promotes Chemokine Expression and Chemotaxis in Part via a Complement C5a--C5aR1 Pathway.

J Immunol 2019 05 5;202(10):2982-2990. Epub 2019 Apr 5.

Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

Biliverdin reductase (BVR)-A is a pleotropic enzyme converting biliverdin to bilirubin and a signaling molecule that has cytoprotective and immunomodulatory effects. We recently showed that biliverdin inhibits the expression of complement activation fragment 5a receptor one (C5aR1) in RAW 264.7 macrophages. In this study, we investigated the role of BVR-A in determining macrophage inflammatory phenotype and function via regulation of C5aR1. We assessed expression of C5aR1, M1-like macrophage markers, including chemokines (RANTES, IP-10), as well as chemotaxis in response to LPS and C5a in bone marrow-derived macrophages from and mice (conditional deletion of BVR-A in myeloid cells). In response to LPS, macrophages isolated from showed significantly elevated levels of C5aR1 as well as chemokines (RANTES, IP10) but not proinflammatory markers, such as iNOS and TNF. An increase in C5aR1 expression was also observed in peritoneal macrophages and several tissues from mice in a model of endotoxemia. In addition, knockdown of BVR-A resulted in enhanced macrophage chemotaxis toward C5a. Part of the effects of BVR-A deletion on chemotaxis and RANTES expression were blocked in the presence of a C5aR1 neutralizing Ab, confirming the role of C5a-C5aR1 signaling in mediating the effects of BVR. In summary, BVR-A plays an important role in regulating macrophage chemotaxis in response to C5a via modulation of C5aR1 expression. In addition, macrophages lacking BVR-A are characterized by the expression of M1 polarization-associated chemokines, the levels of which depend in part on C5aR1 signaling.
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http://dx.doi.org/10.4049/jimmunol.1701443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504595PMC
May 2019

Bilirubin, a Cardiometabolic Signaling Molecule.

Hypertension 2018 10;72(4):788-795

Department of Physiology and Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson (D.E.S.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205727PMC
October 2018

Bilirubin, a new therapeutic for kidney transplant?

Transplant Rev (Orlando) 2018 10 28;32(4):234-240. Epub 2018 Jun 28.

Department of Urology and Renal Transplant, Toledo, OH 43614, USA; Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA. Electronic address:

In patients with end-stage renal disease, kidney transplantation has been associated with numerous benefits, including increased daily activity, and better survival rates. However, over 20% of kidney transplants result in rejection within five years. Rejection is primarily due to a hypersensitive immune system and ischemia/reperfusion injury. Bilirubin has been shown to be a potent antioxidant that is capable of potentially reversing or preventing damage from reactive oxygen species generated from ischemia and reperfusion. Additionally, bilirubin has several immunomodulatory effects that can dampen the immune system to promote organ acceptance. Increased bilirubin has also been shown to have a positive impact on renal hemodynamics, which is critical post-transplantation. Lastly, bilirubin levels have been correlated with biomarkers of successful transplantation. In this review, we discuss a multitude of potentially beneficial effects that bilirubin has on kidney acceptance of transplantation based on numerous clinical trials and animal models. Exogenous bilirubin delivery or increasing endogenous levels pre- or post-transplantation may have therapeutic benefits.
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http://dx.doi.org/10.1016/j.trre.2018.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535229PMC
October 2018

Loss of biliverdin reductase-A promotes lipid accumulation and lipotoxicity in mouse proximal tubule cells.

Am J Physiol Renal Physiol 2018 08 4;315(2):F323-F331. Epub 2018 Apr 4.

Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center , Jackson, Mississippi.

Obesity and increased lipid availability have been implicated in the development and progression of chronic kidney disease. One of the major sites of renal lipid accumulation is in the proximal tubule cells of the kidney, suggesting that these cells may be susceptible to lipotoxicity. We previously demonstrated that loss of hepatic biliverdin reductase A (BVRA) causes fat accumulation in livers of mice on a high-fat diet. To determine the role of BVRA in mouse proximal tubule cells, we generated a CRISPR targeting BVRA for a knockout in mouse proximal tubule cells (BVRA KO). The BVRA KO cells had significantly less metabolic potential and mitochondrial respiration, which was exacerbated by treatment with palmitic acid, a saturated fatty acid. The BVRA KO cells also showed increased intracellular triglycerides which were associated with higher fatty acid uptake gene cluster of differentiation 36 as well as increased de novo lipogenesis as measured by higher neutral lipids. Additionally, neutrophil gelatinase-associated lipocalin 1 expression, annexin-V FITC staining, and lactate dehydrogenase assays all demonstrated that BVRA KO cells are more sensitive to palmitic acid-induced lipotoxicity than wild-type cells. Phosphorylation of BAD which plays a role in cell survival pathways, was significantly reduced in palmitic acid-treated BVRA KO cells. These data demonstrate the protective role of BVRA in proximal tubule cells against saturated fatty acid-induced lipotoxicity and suggest that activating BVRA could provide a benefit in protecting from obesity-induced kidney injury.
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http://dx.doi.org/10.1152/ajprenal.00495.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139518PMC
August 2018

Biliverdin reductase and bilirubin in hepatic disease.

Am J Physiol Gastrointest Liver Physiol 2018 06 1;314(6):G668-G676. Epub 2018 Mar 1.

Department of Physiology and Pharmacology, Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine , Toledo, Ohio.

The buildup of fat in the liver (hepatic steatosis) is the first step in a series of incidents that may drive hepatic disease. Obesity is the leading cause of nonalcoholic fatty liver disease (NAFLD), in which hepatic steatosis progresses to liver disease. Chronic alcohol exposure also induces fat accumulation in the liver and shares numerous similarities to obesity-induced NAFLD. Regardless of whether hepatic steatosis is due to obesity or long-term alcohol use, it still may lead to hepatic fibrosis, cirrhosis, or possibly hepatocellular carcinoma. The antioxidant bilirubin and the enzyme that generates it, biliverdin reductase A (BVRA), are components of the heme catabolic pathway that have been shown to reduce hepatic steatosis. This review discusses the roles for bilirubin and BVRA in the prevention of steatosis, their functions in the later stages of liver disease, and their potential therapeutic application.
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http://dx.doi.org/10.1152/ajpgi.00026.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032063PMC
June 2018

Bilirubin in the Liver-Gut Signaling Axis.

Trends Endocrinol Metab 2018 03 3;29(3):140-150. Epub 2018 Feb 3.

Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA. Electronic address:

Bilirubin is a component of the heme catabolic pathway that is essential for liver function and has been shown to reduce hepatic fat accumulation. High plasma bilirubin levels are reflective of liver disease due to an injurious effect on hepatocytes. In healthy liver, bilirubin is conjugated and excreted to the intestine and converted by microbes to urobilinoids, which are reduced to the predominant pigment in feces, stercobilin, or reabsorbed. The function of urobilinoids in the gut or their physiological relevance of reabsorption is not well understood. In this review, we discuss the relationship of hepatic bilirubin signaling to the intestinal microbiota and its regulation of the liver-gut axis, as well as its capacity to mediate these processes.
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http://dx.doi.org/10.1016/j.tem.2018.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831340PMC
March 2018

A Novel Fluorescence-Based Assay for the Measurement of Biliverdin Reductase Activity.

React Oxyg Species (Apex) 2018 1;5(13):35-45. Epub 2018 Jan 1.

Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216.

Biliverdin reductase (BVR) is the enzyme responsible for the last step in the production of bilirubin from the breakdown of heme. Bilirubin is one of the most potent antioxidant molecules in the body. Monitoring BVR activity is essential in studying the antioxidant capacity of cells and tissues. Traditional methods of determining BVR activity have relied on the measurement of bilirubin converted from biliverdin using absorbance spectroscopy. The approach has limited sensitivity and requires large quantities of cells or tissues. We have developed a novel fluorescence-based method utilizing the eel protein, UnaG, for the detection of bilirubin produced by BVR. The UnaG protein only fluoresces by the induction of bilirubin. We have also used this approach to measure intracellular bilirubin content of cultured cells. We validated this assay using cell lysates from mouse liver and immortalized murine hepatic cell line (Hepa1c1c7) and kidney cell line (MCT) in which BVR isoform A (BVRA) was either knocked out via CRISPR or stably overexpressed by lentivirus. Also, we tested the method using previously reported putative BVRA inhibitors, Closantel and Ebselen. These studies show a new method for measuring bilirubin intracellularly and in lysates.
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http://dx.doi.org/10.20455/ros.2018.809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785779PMC
January 2018

Heme oxygenase-1 is a potent inhibitor of placental ischemia-mediated endothelin-1 production in cultured human glomerular endothelial cells.

Am J Physiol Regul Integr Comp Physiol 2018 03 6;314(3):R427-R432. Epub 2017 Dec 6.

Department of Physiology and Biophysics, University of Mississippi Medical Center , Jackson, Mississippi.

Preeclampsia is a pregnancy-specific disorder of maternal hypertension and reduced renal hemodynamics linked to reduced endothelial function. Placental ischemia is thought to be the culprit of this disease, as it causes the release of factors like tumor necrosis factor (TNF)-α that induce vascular endothelin-1 (ET-1) production. Interestingly, placental ischemia-induced hypertension in rats [reduced uterine perfusion pressure (RUPP) model] is abolished by ET receptor blockade, suggesting a critical role for ET-1. Although it has been found that systemic induction of heme oxygenase (HO)-1 is associated with reduced ET-1 production and attenuated hypertension, it is unclear whether HO-1 directly modulates the increased ET-1 response to placental factors. We tested the hypothesis that HO-1 or its metabolites inhibit ET-1 production in human glomerular endothelial cells induced by serum of RUPP rats or TNF-α. Serum (5%) from RUPP hypertensive (mean arterial blood pressure 119 ± 9 mmHg) vs. normotensive pregnant (NP, 101 ± 6 mmHg, P < 0.001) rats increased ET-1 production (RUPP 168.8 ± 18.1 pg/ml, NP 80.3 ± 22.7 pg/ml, P < 0.001, n = 12/group). HO-1 induction [25 µM cobalt photoporphyrin (CoPP)] abolished RUPP serum-induced ET-1 production (1.6 ± 0.8 pg/ml, P < 0.001), whereas bilirubin (10 µM) significantly attenuated ET-1 release (125.3 ± 5.2 pg/ml, P = 0.005). Furthermore, TNF-α-induced ET-1 production (TNF-α 31.0 ± 8.4 vs. untreated 7.5 ± 0.4 pg/ml, P < 0.001) was reduced by CoPP (1.5 ± 0.8 pg/ml, P < 0.001) and bilirubin (10.5 ± 4.3 pg/ml, P < 0.001). These results suggest that circulating factors released during placental ischemia target the maternal glomerular endothelium to increase ET-1, and that pharmacological induction of HO-1 or bilirubin could be a treatment strategy to block this prohypertensive pathway in preeclampsia.
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http://dx.doi.org/10.1152/ajpregu.00370.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899255PMC
March 2018

Carbon Monoxide Releasing Molecules Blunt Placental Ischemia-Induced Hypertension.

Am J Hypertens 2017 Sep;30(9):931-937

Departments of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.

Background: Preeclampsia is a pregnancy complication which manifests as new-onset hypertension, proteinuria, and a spectrum of other symptoms. While the underlying causes are still a subject of much debate, it is commonly believed that placental ischemia is a central cause. The ischemic placenta secretes factors which are believed to be responsible for the maternal syndrome; most notably the anti-angiogenic protein soluble fms-like tyrosine kinase 1 (sFlt-1). We have reported that induction of the carbon monoxide (CO) producing protein heme oxygenase-1 restored angiogenic imbalance and reduced blood pressure in a rat model of placental ischemia, and that CO blocks hypoxia-induced sFlt-1 production from placental tissue in vitro. We therefore hypothesized that direct administration of CO by a CO-releasing molecule (CORM) would blunt the placental ischemia-induced increase in sFlt-1 and thus the hypertension characteristic of this model.

Methods: We administered a soluble CO donor molecule (CORM-3) daily i.v. in control animals or those undergoing placental ischemia from GD14. Blood pressure and renal function were measured on GD19, and angiogenic markers measured by ELISA.

Results: Interestingly, though we found that CORM administration significantly blunted the hypertensive response to placental ischemia, there was no concomitant normalization of sFlt-1 in either the placenta or maternal circulation. We did find, however, that CORM administration caused a significant increase in glomerular filtration rate, presumably by vasodilation of the renal arteries and increased renal plasma flow.

Conclusions: All in all these data suggest that administration of CO by CORMs do lower blood pressure during placental ischemia mechanisms independent of changes in angiogenic balance.
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http://dx.doi.org/10.1093/ajh/hpx070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861582PMC
September 2017

Sex-Dependent Effects of HO-1 Deletion from Adipocytes in Mice.

Int J Mol Sci 2017 Mar 11;18(3). Epub 2017 Mar 11.

Department of Physiology & Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216, USA.

Induction of heme oxygenase-1 (HO-1) has been demonstrated to decrease body weight and improve insulin sensitivity in several models of obesity in rodents. To further study the role of HO-1 in adipose tissue, we created an adipose-specific HO-1 knockout mouse model. Male and female mice were fed either a control or a high-fat diet for 30 weeks. Body weights were measured weekly and body composition, fasting blood glucose and insulin levels were determined every six weeks. Adipocyte-specific knockout of HO-1 had no significant effect on body weight in mice fed a high-fat diet but increased body weight in female mice fed a normal-fat diet. Although body weights were not different in females fed a high fat diet, loss of HO-1 in adipocytes resulted in significant alterations in body composition. Adipose-specific HO-1 knockout resulted in increased fasting hyperglycemia and insulinemia in female but not male mice on both diets. Adipose-specific knockout of HO-1 resulted in a significant loss of HO activity and a decrease in the protein levels of adiponectin in adipose tissue. These results demonstrate that loss of HO-1 in adipocytes has greater effects on body fat and fasting hyperglycemia in a sex-dependent fashion and that expression of HO-1 in adipose tissue may have a greater protective role in females as compared to males.
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http://dx.doi.org/10.3390/ijms18030611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372627PMC
March 2017

Mice with hyperbilirubinemia due to Gilbert's syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARα.

Am J Physiol Endocrinol Metab 2017 04 17;312(4):E244-E252. Epub 2017 Jan 17.

Department of Physiology and Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi;

Gilbert's syndrome in humans is derived from a polymorphism (TA repeat) in the hepatic gene that results in decreased conjugation and increased levels of unconjugated bilirubin. Recently, we have shown that bilirubin binds directly to the fat-burning nuclear peroxisome proliferator-activated receptor-α (PPARα). Additionally, we have shown that serine 73 phosphorylation [Ser(P)] of PPARα decreases activity by reducing its protein levels and transcriptional activity. The aim of this study was to determine whether humanized mice with the Gilbert's polymorphism (HuUGT*28) have increased PPARα activation and reduced hepatic fat accumulation. To determine whether humanized mice with Gilbert's mutation (HuUGT*28) have reduced hepatic lipids, we placed them and C57BL/6J control mice on a high-fat (60%) diet for 36 wk. Body weights, fat and lean mass, and fasting blood glucose and insulin levels were measured every 6 wk throughout the investigation. At the end of the study, hepatic lipid content was measured and PPARα regulated genes as well as immunostaining of Ser(P) PPARα from liver sections. The HuUGT*28 mice had increased serum bilirubin, lean body mass, decreased fat mass, and hepatic lipid content as well as lower serum glucose and insulin levels. Also, the HuUGT*28 mice had reduced Ser(P) PPARα immunostaining in livers and increased PPARα transcriptional activity compared with controls. A chronic but mild endogenous increase in unconjugated hyperbiliubinemia protects against hepatic steatosis through a reduction in Ser(P) PPARα, causing an increase in PPARα transcriptional activity.
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http://dx.doi.org/10.1152/ajpendo.00396.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406988PMC
April 2017

Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α.

J Biol Chem 2016 Dec 26;291(50):25776-25788. Epub 2016 Oct 26.

Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, Ohio 43614,

Glucocorticoids (GCs) regulate energy supply in response to stress by increasing hepatic gluconeogenesis during fasting. Long-term GC treatment induces hepatic steatosis and weight gain. GC signaling is coordinated via the GC receptor (GR) GRα, as the GRβ isoform lacks a ligand-binding domain. The roles of the GR isoforms in the regulation of lipid accumulation is unknown. The purpose of this study was to determine whether GRβ inhibits the actions of GCs in the liver, or enhances hepatic lipid accumulation. We show that GRβ expression is increased in adipose and liver tissues in obese high-fat fed mice. Adenovirus-mediated delivery of hepatic GRβ overexpression (GRβ-Ad) resulted in suppression of gluconeogenic genes and hyperglycemia in mice on a regular diet. Furthermore, GRβ-Ad mice had increased hepatic lipid accumulation and serum triglyceride levels possibly due to the activation of NF-κB signaling and increased tumor necrosis factor α (TNFα) and inducible nitric-oxide synthase expression, indicative of enhanced M1 macrophages and the development of steatosis. Consequently, GRβ-Ad mice had increased glycogen synthase kinase 3β (GSK3β) activity and reduced hepatic PPARα and fibroblast growth factor 21 (FGF21) expression and lower serum FGF21 levels, which are two proteins known to increase during fasting to enhance the burning of fat by activating the β-oxidation pathway. In conclusion, GRβ antagonizes the GC-induced signaling during fasting via GRα and the PPARα-FGF21 axis that reduces fat burning. Furthermore, hepatic GRβ increases inflammation, which leads to hepatic lipid accumulation.
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http://dx.doi.org/10.1074/jbc.M116.752311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203696PMC
December 2016

Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3β Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) α.

J Biol Chem 2016 Nov 10;291(48):25179-25191. Epub 2016 Oct 10.

From the Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi 39216,

Non-alcoholic fatty liver disease is the most rapidly growing form of liver disease and if left untreated can result in non-alcoholic steatohepatitis, ultimately resulting in liver cirrhosis and failure. Biliverdin reductase A (BVRA) is a multifunctioning protein primarily responsible for the reduction of biliverdin to bilirubin. Also, BVRA functions as a kinase and transcription factor, regulating several cellular functions. We report here that liver BVRA protects against hepatic steatosis by inhibiting glycogen synthase kinase 3β (GSK3β) by enhancing serine 9 phosphorylation, which inhibits its activity. We show that GSK3β phosphorylates serine 73 (Ser(P)) of the peroxisome proliferator-activated receptor α (PPARα), which in turn increased ubiquitination and protein turnover, as well as decreased activity. Interestingly, liver-specific BVRA KO mice had increased GSK3β activity and Ser(P) of PPARα, which resulted in decreased PPARα protein and activity. Furthermore, the liver-specific BVRA KO mice exhibited increased plasma glucose and insulin levels and decreased glycogen storage, which may be due to the manifestation of hepatic steatosis observed in the mice. These findings reveal a novel BVRA-GSKβ-PPARα axis that regulates hepatic lipid metabolism and may provide unique targets for the treatment of non-alcoholic fatty liver disease.
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http://dx.doi.org/10.1074/jbc.M116.731703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122784PMC
November 2016