Aberrant Hepatic Expression of PPARγ2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance. The peroxisome proliferator-activated receptor (PPAR) activators, thiazolidinediones, (TZDs), are insulin sensitizers used as a treatment for NAFLD. However, TZDs are a controversial treatment for NAFLD because of conflicting results regarding hepatic steatosis and fibrosis. To evaluate a possible effective drug for treatment of NAFLD, we investigated the effects of a newly developed TZD, lobeglitazone, with an emphasis on hepatic lipid metabolism. Lobeglitazone treatment for 4 weeks in high fat diet- (HFD-) induced obese mice (HL group) improved insulin resistance and glucose intolerance compared to HFD-induced obese mice (HU group). The gene levels related to hepatic gluconeogenesis also decreased after treatment by lobeglitazone. The livers of mice in the HL group showed histologically reduced lipid accumulation, with lowered total plasma cholesterol and triglyceride levels. In addition, the HL group significantly decreased the hepatic expression of genes associated with lipid synthesis, cholesterol biosynthesis, and lipid droplet development and increased the hepatic expression of genes associated with fatty acid β-oxidation, thus suggesting that lobeglitazone decreased hepatic steatosis and reversed hepatic lipid dysregulation. Livers with steatohepatitis contained increased levels of PPARγ and phosphorylated PPARγ at serine 273, leading to downregulation of expression of genes associated with insulin sensitivity. Notably, the treatment of lobeglitazone increased the protein levels of PPARα and diminished levels of PPARγ phosphorylated at serine 273, which were increased by a HFD, suggesting that induction of PPARα and posttranslational modification of PPARγ in livers by lobeglitazone might be an underlying mechanism of the improvement seen in NAFLD. Taken together, our data showed that lobeglitazone might be an effective treatment for NAFLD.

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Mitochondrial stress protein HSP60 regulates ER stress-induced hepatic lipogenesis

Journal of Molecular Endocrinology ◽

10.1530/jme-19-0207 ◽

2020 ◽

Vol 64 (2) ◽

pp. 67-75 ◽

Cited By ~ 4

Author(s):

Ting Xiao ◽

Xiuci Liang ◽

Hailan Liu ◽

Feng Zhang ◽

Wen Meng ◽

...

Keyword(s):

Insulin Resistance ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Hepatic Steatosis ◽

Molecular Mechanisms ◽

Stress Protein ◽

Hepatic Lipogenesis ◽

Mitochondrial Stress ◽

Hsp60 Expression ◽

Mouse Hepatocytes

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are associated with hepatic steatosis and insulin resistance. Molecular mechanisms underlying ER stress and/or mitochondrial dysfunction that cause metabolic disorders and hepatic steatosis remain to be fully understood. Here, we found that a high fat diet (HFD) or chemically induced ER stress can stimulate mitochondrial stress protein HSP60 expression, impair mitochondrial respiration, and decrease mitochondrial membrane potential in mouse hepatocytes. HSP60 overexpression promotes ER stress and hepatic lipogenic protein expression and impairs insulin signaling in mouse hepatocytes. Mechanistically, HSP60 regulates ER stress-induced hepatic lipogenesis via the mTORC1-SREBP1 signaling pathway. These results suggest that HSP60 is an important ER and mitochondrial stress cross-talking protein and may control ER stress-induced hepatic lipogenesis and insulin resistance.

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Time-restricted feeding improves insulin resistance and hepatic steatosis in a mouse model of postmenopausal obesity

Metabolism ◽

10.1016/j.metabol.2016.09.006 ◽

2016 ◽

Vol 65 (12) ◽

pp. 1743-1754 ◽

Cited By ~ 35

Author(s):

Heekyung Chung ◽

Winjet Chou ◽

Dorothy D. Sears ◽

Ruth E. Patterson ◽

Nicholas J.G. Webster ◽

...

Keyword(s):

Insulin Resistance ◽

Mouse Model ◽

Hepatic Steatosis ◽

Restricted Feeding ◽

Postmenopausal Obesity

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Inducible hepatic expression of CREBH mitigates diet-induced obesity, insulin resistance and hepatic steatosis in mice

Journal of Biological Chemistry ◽

10.1016/j.jbc.2021.100815 ◽

2021 ◽

pp. 100815

Author(s):

Christopher S. Krumm ◽

Xu Xu ◽

Curtis J. Bare ◽

Corey D. Holman ◽

Sander Kersten ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

Hepatic Expression ◽

Diet Induced Obesity

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Effect of acetylsalicylic acid on inflamed adipose tissue. Insulin resistance and hepatic steatosis in a mouse model of diet-induced obesity

Life Sciences ◽

10.1016/j.lfs.2020.118618 ◽

2021 ◽

Vol 264 ◽

pp. 118618 ◽

Cited By ~ 1

Author(s):

Claudia Sardi ◽

Elisa Martini ◽

Tommaso Mello ◽

Simone Camelliti ◽

Lucia Sfondrini ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Mouse Model ◽

Acetylsalicylic Acid ◽

Hepatic Steatosis ◽

Diet Induced Obesity

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Molecular Mechanisms of Hepatic Steatosis and Insulin Resistance in the AGPAT2-Deficient Mouse Model of Congenital Generalized Lipodystrophy

Cell Metabolism ◽

10.1016/j.cmet.2009.01.002 ◽

2009 ◽

Vol 9 (2) ◽

pp. 165-176 ◽

Cited By ~ 160

Author(s):

Víctor A. Cortés ◽

David E. Curtis ◽

Suja Sukumaran ◽

Xinli Shao ◽

Vinay Parameswara ◽

...

Keyword(s):

Insulin Resistance ◽

Mouse Model ◽

Hepatic Steatosis ◽

Molecular Mechanisms ◽

Deficient Mouse ◽

Congenital Generalized Lipodystrophy

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

Molecular Systems Biology ◽

10.15252/msb.20209684 ◽

2021 ◽

Vol 17 (1) ◽

Author(s):

Frode Norheim ◽

Karthickeyan Chella Krishnan ◽

Thomas Bjellaas ◽

Laurent Vergnes ◽

Calvin Pan ◽

...

Keyword(s):

Insulin Resistance ◽

Mouse Model ◽

Hepatic Steatosis ◽

Genetic Regulation ◽

Liver Lipids

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Metabolic PCOS Features Are Ameliorated by Mitochondrial Uncoupler BAM15 in a PCOS Mouse Model

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1565 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A769-A770

Author(s):

Valentina Rodriguez Paris ◽

Stephanie J Alexopoulos ◽

Ying Hu ◽

Divya P Shah ◽

Ali Aflatounian ◽

...

Keyword(s):

Insulin Resistance ◽

Weight Loss ◽

Mouse Model ◽

Hepatic Steatosis ◽

Animal Studies ◽

Metabolic Diseases ◽

Polycystic Ovary ◽

Mesenteric Fat ◽

Adipocyte Hypertrophy ◽

Mitochondrial Uncoupler

Abstract Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterized by endocrine, reproductive and metabolic dysfunction. At present, there is no cure for PCOS and current treatments are suboptimal. Obesity and adverse metabolic features are prevalent in women with PCOS, with weight loss having a beneficial effect on PCOS features. The use of dietary interventions aimed at weight loss have low long-term compliance in women suffering from PCOS. Recent data from animal studies has shown that a small molecule mitochondrial uncoupler, BAM15, is an effective method to pharmacologically treat obesity and metabolic diseases. Therefore, the aim of this study was to investigate the efficacy of BAM15 to ameliorate PCOS-traits in a hyperandrogenic PCOS mouse model. As expected, exposure of female mice to dihydrotestosterone (DHT) induced the PCOS metabolic features of increased body weight (P<0.05), lean mass (P<0.001), increased parametrial and mesenteric fat pad weights (both P<0.05) and adipocyte hypertrophy (P<0.05). Additionally, DHT-induced PCOS mice exhibited insulin resistance measured by HOMA-IR, increased cholesterol and fasting triglyceride levels and hepatic steatosis (all P<0.05). In contrast, DHT-induced PCOS females treated with BAM15 displayed body weights which were comparable with controls, a significant decrease in parametrial and mesenteric fat depot weights (P<0.05) and reduced adipocyte hypertrophy. Furthermore, BAM15 treatment decreased insulin resistance, cholesterol and fasting triglyceride levels, as well as the degree of hepatic steatosis observed in PCOS females, to levels comparable with controls. PCOS mice presented the reproductive PCOS traits of irregular cycles and ovulatory dysfunction, however BAM15 did not improve these PCOS traits. These findings demonstrate that the pharmacologic mitochondrial uncoupler BAM15 is able to ameliorate metabolic PCOS features in a hyperandrogenic PCOS mouse model. These data provide compelling evidence to support BAM15 as a potential innovative and viable therapeutic approach to manage metabolic traits associated with PCOS.

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Sleeve Gastroplasty Combined with the NLRP3 Inflammasome Inhibitor CY-09 Reduces Body Weight, Improves Insulin Resistance and Alleviates Hepatic Steatosis in Mouse Model

Obesity Surgery ◽

10.1007/s11695-020-04571-8 ◽

2020 ◽

Vol 30 (9) ◽

pp. 3435-3443 ◽

Cited By ~ 1

Author(s):

Kangyue Sun ◽

Jing Wang ◽

Zhixian Lan ◽

Ling Li ◽

Yadong Wang ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Mouse Model ◽

Hepatic Steatosis ◽

Nlrp3 Inflammasome ◽

Sleeve Gastroplasty

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The endothelial dysfunction blocker CU06-1004 ameliorates choline-deficient L-amino acid diet-induced non-alcoholic steatohepatitis in mice

PLoS ONE ◽

10.1371/journal.pone.0243497 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0243497

Author(s):

Cho-Rong Bae ◽

Haiying Zhang ◽

Young-Guen Kwon

Keyword(s):

Amino Acid ◽

Endothelial Dysfunction ◽

Mouse Model ◽

Hepatic Steatosis ◽

Hepatic Fibrosis ◽

Liver Sinusoidal Endothelial Cell ◽

Alcoholic Fatty Liver ◽

Hepatic Expression ◽

Alcoholic Steatohepatitis ◽

Expression Of Genes

Non-alcoholic steatohepatitis (NASH) is a severe, advanced form of non-alcoholic fatty liver disease (NAFLD) that is associated with features of metabolic syndrome and characterized by hepatic steatosis, inflammation, and fibrosis. In addition, NASH is associated with endothelial dysfunction within the hepatic vasculature. Treatment with CU06-1004 (previously called Sac-1004) ameliorates endothelial dysfunction by inhibiting hyperpermeability and inflammation. In this study, we investigated the protective effects of CU06-1004 in a choline-deficient L-amino acid (CDAA)-induced mouse model of NASH for 3 or 6 weeks. Specifically, we evaluated the effects of CU06-1004 on lipid accumulation, inflammation, hepatic fibrosis, and liver sinusoidal endothelial cell (LSEC) capillarization through biochemical analysis, immunohistochemistry, and real-time PCR. We found that the administration of CU06-1004 to mice improved liver triglyceride (TG) and serum alanine aminotransferase (ALT) in this CDAA-induced model of NASH for 6 weeks. In groups of NASH induced mice for both 3 and 6 weeks, CU06-1004 significantly reduced the hepatic expression of genes related to lipogenesis, inflammation, and cell adhesion. However, expression of genes related to hepatic fibrosis and vascular endothelial changes were only decreased in animals with mild NASH. These results suggest that the administration of CU06-1004 suppresses hepatic steatosis, inflammation, fibrosis, and LSEC capillarization in a CDAA-induced mouse model of NASH. This suggests that CU06-1004 has therapeutic potential for the treatment of mild NASH.

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