scholarly journals Loss of Hepatocyte-Specific PPARγ Expression Ameliorates Early Events of Steatohepatitis in Mice Fed the Methionine and Choline-Deficient Diet

PPAR Research ◽  
2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Jose Cordoba-Chacon
Keyword(s):  
Fatty Acid ◽  
Molecular Mechanisms ◽  
Fatty Acid Uptake ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Deficient Diet ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Cd36 Expression ◽  
Pparγ Expression

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. To date, there is not a specific and approved treatment for NAFLD yet, and therefore, it is important to understand the molecular mechanisms that lead to the progression of NAFLD. Methionine- and choline-deficient (MCD) diets are used to reproduce some features of NAFLD in mice. MCD diets increase the expression of hepatic peroxisome proliferator-activated receptor gamma (PPARγ, Pparg) and the fatty acid translocase (CD36, Cd36) which could increase hepatic fatty acid uptake and promote the progression of NAFLD in mice and humans. In this study, we assessed the contribution of hepatocyte-specific PPARγ and CD36 expression to the development of early events induced by the MCD diet. Specifically, mice with adult-onset, hepatocyte-specific PPARγ knockout with and without hepatocyte CD36 overexpression were fed a MCD diet for three weeks. Hepatocyte PPARγ and/or CD36 expression did not contribute to the development of steatosis induced by the MCD diet. However, the expression of inflammatory and fibrogenic genes seems to be dependent on the expression of hepatocyte PPARγ and CD36. The expression of PPARγ and CD36 in hepatocytes may be relevant in the regulation of some features of NAFLD and steatohepatitis.

scholarly journals Endogenous Peroxisome Proliferator-Activated Receptor-γ Augments Fatty Acid Uptake in Oxidative Muscle

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5374-5383 ◽  
Author(s):  
Andrew W. Norris ◽  
Michael F. Hirshman ◽  
Jianrong Yao ◽  
Niels Jessen ◽  
Nicolas Musi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Uptake ◽  
Transport Protein ◽  
Fatty Acid Transport ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Acid Transport ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonesterified Fatty Acids ◽  
Fatty Acid Transport Protein

In the setting of insulin resistance, agonists of peroxisome proliferator-activated receptor (PPAR)-γ restore insulin action in muscle and promote lipid redistribution. Mice with muscle-specific knockout of PPARγ (MuPPARγKO) develop excess adiposity, despite reduced food intake and normal glucose disposal in muscle. To understand the relation between muscle PPARγ and lipid accumulation, we studied the fuel energetics of MuPPARγKO mice. Compared with controls, MuPPARγKO mice exhibited significantly increased ambulatory activity, muscle mitochondrial uncoupling, and respiratory quotient. Fitting with this latter finding, MuPPARγKO animals compared with control siblings exhibited a 25% reduction in the uptake of the fatty acid tracer 2-bromo-palmitate (P < 0.05) and a 13% increase in serum nonesterified fatty acids (P = 0.05). These abnormalities were associated with no change in AMP kinase (AMPK) phosphorylation, AMPK activity, or phosphorylation of acetyl-CoA carboxylase in muscle and occurred despite increased expression of fatty acid transport protein 1. Palmitate oxidation was not significantly altered in MuPPARγKO mice despite the increased expression of several genes promoting lipid oxidation. These data demonstrate that PPARγ, even in the absence of exogenous activators, is required for normal rates of fatty acid uptake in oxidative skeletal muscle via mechanisms independent of AMPK and fatty acid transport protein 1. Thus, when PPARγ activity in muscle is absent or reduced, there will be decreased fatty acid disposal leading to diminished energy utilization and ultimately adiposity.

scholarly journals The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xinzhi Li ◽  
Bingchuan Yuan ◽  
Min Lu ◽  
Yuqin Wang ◽  
Na Ding ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Nonalcoholic Steatohepatitis ◽  
Promoter Region ◽  
Molecular Mechanisms ◽  
Fatty Acid Uptake ◽  
Chromatin Accessibility ◽  
Negative Regulator ◽  
Acid Uptake ◽  
Nonalcoholic Fatty Liver ◽  
Specific Deletion

AbstractNonalcoholic steatohepatitis (NASH) is a key step in the progression of nonalcoholic fatty liver (NAFL) to cirrhosis. However, the molecular mechanisms of the NAFL-to-NASH transition are largely unknown. Here, we identify methyltransferase like 3 (METTL3) as a key negative regulator of NASH pathogenesis. Hepatocyte-specific deletion of Mettl3 drives NAFL-to-NASH progression by increasing CD36-mediated hepatic free fatty acid uptake and CCL2-induced inflammation, which is due to increased chromatin accessibility in the promoter region of Cd36 and Ccl2. Antibody blockade of CD36 and CCL2 ameliorates NASH progression in hepatic Mettl3 knockout mice. Hepatic overexpression of Mettl3 protects against NASH progression by inhibiting the expression of CD36 and CCL2. Mechanistically, METTL3 directly binds to the promoters of the Cd36 and Ccl2 genes and recruits HDAC1/2 to induce deacetylation of H3K9 and H3K27 in  their promoters, thus suppressing Cd36 and Ccl2 transcription. Furthermore, METTL3 is translocated from the nucleus to the cytosol in NASH, which is associated with CDK9-mediated phosphorylation of METTL3. Our data reveal a mechanism by which METTL3 negatively regulates hepatic Cd36 and Ccl2 gene transcription via a histone modification pathway for protection against NASH progression.

scholarly journals Peroxisome Proliferator-Activated Receptor γ Decouples Fatty Acid Uptake from Lipid Inhibition of Insulin Signaling in Skeletal Muscle

2012 ◽  
Vol 26 (6) ◽  
pp. 977-988 ◽  
Author(s):  
Shanming Hu ◽  
Jianrong Yao ◽  
Alexander A. Howe ◽  
Brandon M. Menke ◽  
William I. Sivitz ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Insulin Signaling ◽  
Fatty Acid Uptake ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Peroxisome Proliferator Activated Receptor

scholarly journals Blocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression

2020 ◽  
Vol 117 (44) ◽  
pp. 27412-27422
Author(s):  
Peng-bo Yang ◽  
Pei-pei Hou ◽  
Fu-yuan Liu ◽  
Wen-bin Hong ◽  
Hang-zi Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Cancer Progression ◽  
Ubiquitin Ligase ◽  
Tumor Development ◽  
Fatty Acid Uptake ◽  
Regulatory Function ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Peroxisome Proliferator Activated Receptor

Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigeneses. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters ofCD36andFABP4to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation. Peroxisome proliferator-activated receptor-γ (PPARγ) played an antagonistic role in this process through binding to Nur77 to facilitate ubiquitin ligase Trim13-mediated ubiquitination and degradation of Nur77. Cocrystallographic and functional analysis revealed that Csn-B, a Nur77-targeting compound, promoted the formation of Nur77 homodimer to prevent PPARγ binding by steric hindrance, thereby strengthening the Nur77’s inhibitory role in breast cancer. Therefore, our study reveals a regulatory function of Nur77 in breast cancer via impeding fatty acid uptake.

Substance P decreases fat storage and increases adipocytokine production in 3T3-L1 adipocytes

2013 ◽  
Vol 304 (4) ◽  
pp. G420-G427 ◽  
Author(s):  
Pierre Miegueu ◽  
David H. St-Pierre ◽  
Marc Lapointe ◽  
Pegah Poursharifi ◽  
HuiLing Lu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Mrna Expression ◽  
Fatty Acid Uptake ◽  
Complement C3 ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant

Obesity, inflammation, and insulin resistance are closely linked. Substance P (SP), via its neurokinin 1 receptor (NK1R), mediates inflammatory and, possibly, neuroendocrine processes. We examined SP effects on lipid storage and cytokine production in 3T3-L1 adipocytes and adipose tissues. 3T3-L1 adipocytes and preadipocytes express NK1R, and 8 days of SP supplementation during differentiation to 3T3-L1 preadipocytes decreased lipid droplet accumulation. SP (10 nM, 24 h) increased lipolysis in primary adipocytes (138 ± 7%, P < 0.05) and reduced fatty acid uptake (−31 ± 7%, P < 0.05) and mRNA expression of the differentiation-related transcription factors peroxisome proliferator-activated receptor-γ type 2 (−64 ± 2%, P < 0.001) and CCAAT enhancer-binding protein (CEBP)-α (−65 ± 2%, P < 0.001) and the lipid storage genes fatty acid-binding protein type 4 (−59 ± 2%, P < 0.001) and diacylglycerol O-acyltransferase-1 (−45 ± 2%, P < 0.01) in 3T3-L1 adipocytes, while CD36, a fatty acid transporter (+82 ± 19%, P < 0.01), was augmented. SP increased secretion of complement C3 (148 ± 15%, P < 0.04), monocyte chemoattractant protein-1 (156 ± 16%, P < 0.03), and keratinocyte-derived chemokine (148 ± 18%, P = 0.045) in 3T3-L1 adipocytes and monocyte chemoattractant protein-1 (496 ± 142%, P < 0.02) and complement C3 (152 ± 25%, P < 0.04) in adipose tissue and primary adipocytes, respectively. These SP effects were accompanied by downregulation of insulin receptor substrate 1 (−82 ± 2%, P < 0.01) and GLUT4 (−76 ± 2%, P < 0.01) mRNA expression, and SP acutely blocked insulin-mediated stimulation of fatty acid uptake and Akt phosphorylation. Although adiponectin secretion was unchanged, mRNA expression was decreased (−86 ± 8%, P < 0.001). In humans, NK1R expression correlates positively with plasma insulin, fatty acid, and complement C3 and negatively with adiponectin, CEBPα, CEBPβ, and peroxisome proliferator-activated receptor-γ mRNA expression in omental, but not subcutaneous, adipose tissue. Our results suggest that, beyond its neuroendocrine and inflammatory effects, SP could also be involved in targeting adipose tissue and influencing insulin resistance.

scholarly journals Downregulation of peroxisome proliferator-activated receptor α and its coactivators in liver and skeletal muscle mediates the metabolic adaptations during lactation in mice

2009 ◽  
Vol 43 (6) ◽  
pp. 241-250 ◽  
Author(s):  
Anke Gutgesell ◽  
Robert Ringseis ◽  
Eileen Schmidt ◽  
Corinna Brandsch ◽  
Gabriele I Stangl ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Target Genes ◽  
Fatty Acid Uptake ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Adaptations

Previous studies have shown that genes involved in fatty acid uptake, fatty acid oxidation, and thermogenesis are downregulated in liver and skeletal muscle of rats during lactation. However, biochemical mechanisms underlying these important metabolic adaptations during lactation have not yet been elucidated. As all these genes are transcriptionally regulated by peroxisome proliferator-activated receptor α (Pparα), we hypothesized that their downregulation is mediated by a suppression of Pparα during lactation. In order to investigate this hypothesis, we performed an experiment with lactating and nonlactating Pparα knockout and corresponding wild-type mice. In wild-type mice, lactation led to a considerable downregulation of Pparα, Ppar coactivators Pgc1α and Pgc1β, and Pparα target genes involved in fatty acid uptake, fatty acid oxidation, and thermogenesis in liver and skeletal muscle (P<0.05). Pparα knockout mice had generally a lower expression of all these Pparα target genes in liver and skeletal muscle. However, in those mice, lactation did not lower the expression of genes involved in fatty acid utilization and thermogenesis in liver and skeletal muscle. Expression levels of Pparα target genes in lactating wild-type mice were similar than in lactating or nonlactating Pparα knockout mice. In conclusion, the present findings suggest that downregulation of Pparα and its coactivators in tissues with high rates of fatty acid catabolism is responsible for the reduced utilization of fatty acids in liver and skeletal muscle and the reduced thermogenesis occurring in the lactating animal, which aim to conserve energy and metabolic substrates for milk production in the mammary gland.

scholarly journals The Lipid Droplet-Associated Protein Adipophilin Is Expressed in Human Trophoblasts and Is Regulated by Peroxisomal Proliferator-Activated Receptor-γ/Retinoid X Receptor

2003 ◽  
Vol 88 (12) ◽  
pp. 6056-6062 ◽  
Author(s):  
Ibrahim Bildirici ◽  
Cheong-Rae Roh ◽  
W. Timothy Schaiff ◽  
Beth M. Lewkowski ◽  
D. Michael Nelson ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Droplet ◽  
Fatty Acid Uptake ◽  
Cellular Fatty Acid ◽  
Retinoid X Receptor ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Lipid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Associated Proteins

Abstract Uptake and transplacental transfer of fatty acids is essential for fetal development. Human adipophilin and its murine ortholog adipocyte differentiation-related protein are lipid droplet-associated proteins that are implicated in cellular fatty acid uptake in adipocytes. The nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) stimulates lipid uptake by adipocytes and enhances differentiation of placental trophoblasts. We therefore hypothesized that adipophilin is expressed in human trophoblasts and that its expression is regulated by PPARγ. We initially determined that adipophilin is expressed in human villous trophoblasts and that adipophilin expression is enhanced during differentiation of cultured primary term human trophoblasts. We also found that exposure of cultured human trophoblasts to the PPARγ ligand troglitazone resulted in a concentration-dependent increase in adipophilin expression. We observed a similar increase with LG268, a ligand for retinoid X receptor (RXR), the heterodimeric partner of PPARγ. Lastly, we demonstrated that ligand-activated PPARγ and RXR stimulated the transcriptional activity of adipophilin promoter in CV-1 cells and in the placental JEG3 cell line. We conclude that the expression of adipophilin is enhanced during trophoblast differentiation and is up-regulated by ligand-activated PPARγ/RXR. Enhanced adipophilin expression may contribute to fatty acid uptake by the placenta.

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