scholarly journals Treatment with Lobeglitazone Attenuates Hepatic Steatosis in Diet-Induced Obese Mice

PPAR Research ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Sorim Choung ◽  
Kyong Hye Joung ◽  
Bo Ram You ◽  
Sang Ki Park ◽  
Hyun Jin Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Plasma Cholesterol ◽  
Cholesterol Biosynthesis ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Expression ◽  
Expression Of Genes

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.

scholarly journals Diet Modifies Pioglitazone’s Influence on Hepatic PPARγ-Regulated Mitochondrial Gene Expression

PPAR Research ◽  
2020 ◽  
Vol 2020 ◽  
pp. 1-20
Author(s):  
Sakil Kulkarni ◽  
Jiansheng Huang ◽  
Eric Tycksen ◽  
Paul F. Cliften ◽  
David A. Rudnick
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Transcriptional Regulation ◽  
Mitochondrial Gene ◽  
Peroxisome Proliferator ◽  
Large Set ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Insulin Resistant

Pioglitazone (Pio) is a thiazolidinedione (TZD) insulin-sensitizing drug whose effects result predominantly from its modulation of the transcriptional activity of peroxisome proliferator-activated-receptor-gamma (PPARγ). Pio is used to treat human insulin-resistant diabetes and also frequently considered for treatment of nonalcoholic steatohepatitis (NASH). In both settings, Pio’s beneficial effects are believed to result primarily from its actions on adipose PPARγ activity, which improves insulin sensitivity and reduces the delivery of fatty acids to the liver. Nevertheless, a recent clinical trial showed variable efficacy of Pio in human NASH. Hepatocytes also express PPARγ, and such expression increases with insulin resistance and in nonalcoholic fatty liver disease (NAFLD). Furthermore, mice that overexpress hepatocellular PPARγ and Pio-treated mice with extrahepatic PPARγ gene disruption develop features of NAFLD. Thus, Pio’s direct impact on hepatocellular gene expression might also be a determinant of this drug’s ultimate influence on insulin resistance and NAFLD. Previous studies have characterized Pio’s PPARγ-dependent effects on hepatic expression of specific adipogenic, lipogenic, and other metabolic genes. However, such transcriptional regulation has not been comprehensively assessed. The studies reported here address that consideration by genome-wide comparisons of Pio’s hepatic transcriptional effects in wildtype (WT) and liver-specific PPARγ-knockout (KO) mice given either control or high-fat (HFD) diets. The results identify a large set of hepatic genes for which Pio’s liver PPARγ-dependent transcriptional effects are concordant with its effects on RXR-DNA binding in WT mice. These data also show that HFD modifies Pio’s influence on a subset of such transcriptional regulation. Finally, our findings reveal a broader influence of Pio on PPARγ-dependent hepatic expression of nuclear genes encoding mitochondrial proteins than previously recognized. Taken together, these studies provide new insights about the tissue-specific mechanisms by which Pio affects hepatic gene expression and the broad scope of this drug’s influence on such regulation.

scholarly journals E3 ubiquitin ligase Grail promotes hepatic steatosis through Sirt1 inhibition

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Pei-Yao Liu ◽  
Cheng-Cheung Chen ◽  
Chia-Ying Chin ◽  
Te-Jung Liu ◽  
Wen-Chiuan Tsai ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Acid Synthesis ◽  
Sirtuin 1 ◽  
Nonalcoholic Fatty Liver ◽  
Expression Of Genes ◽  
Hepatic Fat ◽  
Underlying Mechanisms

AbstractIn obese adults, nonalcoholic fatty liver disease (NAFLD) is accompanied by multiple metabolic dysfunctions. Although upregulated hepatic fatty acid synthesis has been identified as a crucial mediator of NAFLD development, the underlying mechanisms are yet to be elucidated. In this study, we reported upregulated expression of gene related to anergy in lymphocytes (GRAIL) in the livers of humans and mice with hepatic steatosis. Grail ablation markedly alleviated the high-fat diet-induced hepatic fat accumulation and expression of genes related to the lipid metabolism, in vitro and in vivo. Conversely, overexpression of GRAIL exacerbated lipid accumulation and enhanced the expression of lipid metabolic genes in mice and liver cells. Our results demonstrated that Grail regulated the lipid accumulation in hepatic steatosis via interaction with sirtuin 1. Thus, Grail poses as a significant molecular regulator in the development of NAFLD.

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

2006 ◽  
Vol 281 (49) ◽  
pp. 37603-37615 ◽  
Author(s):  
Yuan-Li Zhang ◽  
Antonio Hernandez-Ono ◽  
Patty Siri ◽  
Stuart Weisberg ◽  
Donna Conlon ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mouse Model ◽  
Hepatic Steatosis ◽  
Hepatic Lipogenesis ◽  
Hepatic Expression

Black rice anthocyanins alleviate hyperlipidemia, liver steatosis and insulin resistance by regulating lipid metabolism and gut microbiota in obese mice

2021 ◽  
Author(s):  
Haizhao Song ◽  
Xinchun Shen ◽  
Yang Zhou ◽  
Xiaodong Zheng
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Gut Microbiota ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Liver Steatosis ◽  
Obese Mice ◽  
Black Rice ◽  
High Fat ◽  
Diet Induced Obesity

Supplementation of black rice anthocyanins (BRAN) alleviated high fat diet-induced obesity, insulin resistance and hepatic steatosis by improvement of lipid metabolism and modification of the gut microbiota.

scholarly journals Impaired cholesterol metabolism in the mice model of cystic fibrosis. A vicious circle?

2019 ◽  
Author(s):  
Felice Amato ◽  
Alice Castaldo ◽  
Giuseppe Castaldo ◽  
Gustavo Cernera ◽  
Gaetano Corso ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Absorption ◽  
Vicious Circle ◽  
Liver Cholesterol ◽  
Mice Model ◽  
Hepatic Expression ◽  
Expression Of Genes ◽  
Low Cholesterol

AbstractPatients with cystic fibrosis (CF) have low cholesterol absorption and, despite enhanced endogenous biosynthesis, low serum cholesterol. Herein, we investigated cholesterol metabolism in a murine CF model in comparison to wild type (WT) testing serum and liver surrogate biomarkers together with the hepatic expression of genes involved in cholesterol metabolism. CF mice display lower sterols absorption and increased endogenous biosynthesis. Subsequently, we evaluated the effects of a cholesterol-supplemented diet on cholesterol metabolism in CF and WT mice. The supplementation in WT mice determines biochemical changes similar to humans. Instead, CF mice with supplementation did not show significant changes, except for serum phytosterols (−50%), liver cholesterol (+35%) and TNFα mRNA expression, that resulted 5-fold higher than in CF without supplementation. However, liver cholesterol in CF mice with supplementation resulted significantly lower compared to WT supplemented mice. This study shows that in CF mice there is a vicious circle in which the altered bile salts synthesis/secretion contribute to reduce cholesterol digestion/absorption. The consequence is the enhanced liver cholesterol biosynthesis that accumulates in the cell triggering inflammation.

A Correlational Study of Hepatic Steatosis (Fatty Liver Disease) and Liver Enzymes (ALT, AST, GGT) In The Scenario of Insulin Resistance Among Young Medicos.

2021 ◽  
Vol 17 (4) ◽  
pp. 717-725
Author(s):  
Samarpita Mukherjee ◽  
Shubhrajit Saha ◽  
Ushasi Banerjee ◽  
Arup Kumar Banerjee ◽  
Ritam Banerjee
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Lifestyle Modifications ◽  
Cross Sectional ◽  
Mean Values ◽  
Nonalcoholic Fatty Liver ◽  
Study Population

Background and Objectives In the last few decades,Nonalcoholic Fatty Liver Disease (NAFLD) has become a common health issue that leads to serious complications like cirrhosis, cardiovascular disease, etc. Insulin resistance (IR) is the key pathogenic factor for NAFLD. The young medicos being habituated in stressful and sedentary lifestyle and representative of the youth as well can fully justify their selection as study population and help to build social awareness by emphasizing the importance of early lifestyle modifications in preventing or delaying the severe complications of NAFLD. This study is aiming to find out if there is any correlation of hepatic steatosis with IR, Alanine Transaminases (ALT), Aspartate Transaminases (AST) or Gama Glutamyl Transferases (GGT) and also to identify if one enzyme is better correlating with hepatic steatosis than others in the scenario of Insulin Resistance among young medicos. METHODS: 132 medical students of North Bengal Medical College, aged between 18-25 years were included in this institution based observational cross-sectional study. Their Fasting Insulin, glucose, ALT, AST, GGT were measured, and IR was calculated by the Homeostatic Assessment of Insulin Resistance (HOMA-IR) calculator. Sonography was done to assess Hepatic steatosis. RESULTS: Among 132 subjects normal, grade 1 and grade 2 fatty changes have been found in 67.4%, 25%, and 7.6% of the study population respectively. The Grouping was done using the cut-off value of IR (i.e. subjects with IR<1.525 vs. IR≥1.525). Significant differences were found in the mean values of ALT, AST, GGT between groups. Significant positive concordances were found between enzymes ALT, GGT, and hepatic steatosis in subjects having IR ≥ 1.525.Regression analysis showed that higher GGT values have a stronger positive correlation with hepatic steatosis than ALT among the same. Interpretation and Conclusion From this study, we can interpret that subjects having higher GGT values are better associated with steatosis than those having higher ALT values and can lead us to the conclusion that GGT might be an important independent marker for NAFLD associated with IR. Furthermore, such observations may suggest considering GGT as a marker for assessing the severity of fatty liver irrespective of etiopathogenesis, though the population-based vivid evaluation is highly recommended.

Abstract 74: Heme Oxygenase-PPARα Induction of FGF21 in Hepatocytes Recruits pAMPK/pAKT and Attenuates Insulin Resistance in Obese Mice

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Terry D Hinds ◽  
Nader G Abraham
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Heme Oxygenase ◽  
Serum Adiponectin ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Hep G2 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose And Lipid Homeostasis

The peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that is known to regulate glucose and lipid homeostasis and increases expression of the hormone fibroblast growth factor 21 (FGF21), which is secreted to blood, increases phosphorylation of AMPK and AKT in adipocytes and has been purported to stimulate adiponectin synthesis. The heme oxygenase (HO) system is functionally important for reducing ROS and inflammation whose induction has been shown to increase serum adiponectin levels and affect lowering of blood glucose and fatty acids. This study was designed to examine the hypothesis that a HO-1-PPARα crosstalk could elevate hepatic FGF21 thus leading to enhanced adiponectin secretion and abatement of metabolic imbalance. Preliminary experiments were conducted in human hepatocellular carcinoma cells (Hep G2) cultured in the absence or presence of the HO-1 inducer, cobalt protoporphyrin (CoPP, 2μmoles/l). A 2.0 fold induction of HO-1 in Hep G2 cells by CoPP (p<0.05) increased expression of FGF21 1.5 fold (n=3, p=0.0119 vs. vehicle control) without affecting PPARα expression. Additional experiments in obese (ob/ob) mice treated with CoPP (5mg/kg/day) resulted in 2 fold (p<0.05) increase of FGF21 mRNA expression in liver as compared to mice treated with the vehicle. These observations were complemented by blood glucose measurements, which showed significant attenuation in obese mice treated with CoPP (vehicle: 285.0±24 vs. CoPP: 160.0±27.3, p<0.05, n= 5), along with enhancement of adiponectin levels in CoPP treated obese mice (p<0.05). Taken together these results demonstrate that HO-1 could increase serum adiponectin levels and insulin sensitivity by elevating hepatic FGF21 levels. Our overall hypothesis is that the HO-1 can stimulate PPARα activity with resultant activation of hepatic FGF21 secretion and that this HO-PPARα-FGF21 axis could work in concert to modulate the development of insulin resistance and diabetes.

scholarly journals Regular exercise potentiates energetically expensive hepatic de novo lipogenesis during early weight regain

2019 ◽  
Vol 317 (5) ◽  
pp. R684-R695
Author(s):  
David M. Presby ◽  
L. Allyson Checkley ◽  
Matthew R. Jackman ◽  
Janine A. Higgins ◽  
Kenneth L. Jones ◽  
...  
Keyword(s):  
Weight Loss ◽  
Energy Expenditure ◽  
De Novo ◽  
Energy Gap ◽  
Cholesterol Biosynthesis ◽  
Density Lipoprotein ◽  
De Novo Lipogenesis ◽  
Positive Energy ◽  
Hepatic Expression ◽  
Expression Of Genes

Exercise is a potent facilitator of long-term weight loss maintenance (WLM), whereby it decreases appetite and increases energy expenditure beyond the cost of the exercise bout. We have previously shown that exercise may amplify energy expenditure through energetically expensive nutrient deposition. Therefore, we investigated the effect of exercise on hepatic de novo lipogenesis (DNL) during WLM and relapse to obesity. Obese rats were calorically restricted with (EX) or without (SED) treadmill exercise (1 h/day, 6 days/wk, 15 m/min) to induce and maintain weight loss. After 6 wk of WLM, subsets of WLM-SED and WLM-EX rats were allowed ad libitum access to food for 1 day to promote relapse (REL). An energy gap-matched group of sedentary, relapsing rats (REL-GM) were provided a diet matched to the positive energy imbalance of the REL-EX rats. During relapse, exercise increased enrichment of hepatic DN-derived lipids and induced hepatic molecular adaptations favoring DNL compared with the gap-matched controls. In the liver, compared with both REL-SED and REL-GM rats, REL-EX rats had lower hepatic expression of genes required for cholesterol biosynthesis; greater hepatic expression of genes that mediate very low-density lipoprotein synthesis and secretion; and greater mRNA expression of Cyp27a1, which encodes an enzyme involved in the biosynthesis of bile acids. Altogether, these data provide compelling evidence that the liver has an active role in exercise-mediated potentiation of energy expenditure during early relapse.

scholarly journals Embryonic exposures to mono-2-ethylhexyl phthalate induce larval steatosis in zebrafish independent of Nrf2a signaling

2020 ◽  
pp. 1-9
Author(s):  
Karilyn E. Sant ◽  
Hadley M. Moreau ◽  
Larissa M. Williams ◽  
Haydee M. Jacobs ◽  
Anna M. Bowsher ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatic Steatosis ◽  
Antioxidant Response ◽  
Abnormal Development ◽  
Fish Length ◽  
Peroxisome Proliferator ◽  
Primary Metabolite ◽  
Peroxisome Proliferator Activated Receptor ◽  
Expression Of Genes ◽  
Ethylhexyl Phthalate

Abstract Mono-2-ethylhexyl phthalate (MEHP) is the primary metabolite of the ubiquitous plasticizer and toxicant, di-2-ethylhexyl phthalate. MEHP exposure has been linked to abnormal development, increased oxidative stress, and metabolic syndrome in vertebrates. Nuclear factor, Erythroid 2 Like 2 (Nrf2), is a transcription factor that regulates gene expression in response to oxidative stress. We investigated the role of Nrf2a in larval steatosis following embryonic exposure to MEHP. Wild-type and nrf2a mutant (m) zebrafish embryos were exposed to 0 or 200 μg/l MEHP from 6 to either 96 (histology) or 120 hours post fertilization (hpf). At 120 hpf, exposures were ceased and fish were maintained in clean conditions until 15 days post fertilization (dpf). At 15 dpf, fish lengths and lipid content were examined, and the expression of genes involved in the antioxidant response and lipid processing was quantified. At 96 hpf, a subset of animals treated with MEHP had vacuolization in the liver. At 15 dpf, deficient Nrf2a signaling attenuated fish length by 7.7%. MEHP exposure increased hepatic steatosis and increased expression of peroxisome proliferator-activated receptor alpha target fabp1a1. Cumulatively, these data indicate that developmental exposure alone to MEHP may increase risk for hepatic steatosis and that Nrf2a does not play a major role in this phenotype.

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