scholarly journals SIRT3 deficiency exacerbates fatty liver by attenuating the HIF1α-LIPIN 1 pathway and increasing CD36 through Nrf2

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Emma Barroso ◽  
Rosalía Rodríguez-Rodríguez ◽  
Mohammad Zarei ◽  
Javier Pizarro-Degado ◽  
Anna Planavila ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Redox Status ◽  
Acid Oxidation ◽  
Standard Diet ◽  
Peroxisome Proliferator ◽  
Lipid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Vldl Receptor

Abstract Background Deficiency of mitochondrial sirtuin 3 (SIRT3), a NAD+-dependent protein deacetylase that maintains redox status and lipid homeostasis, contributes to hepatic steatosis. In this study, we investigated additional mechanisms that might play a role in aggravating hepatic steatosis in Sirt3-deficient mice fed a high-fat diet (HFD). Methods Studies were conducted in wild-type (WT) and Sirt3−/− mice fed a standard diet or a HFD and in SIRT3-knockdown human Huh-7 hepatoma cells. Results Sirt3−/− mice fed a HFD presented exacerbated hepatic steatosis that was accompanied by decreased expression and DNA-binding activity of peroxisome proliferator-activated receptor (PPAR) α and of several of its target genes involved in fatty acid oxidation, compared to WT mice fed the HFD. Interestingly, Sirt3 deficiency in liver and its knockdown in Huh-7 cells resulted in upregulation of the nuclear levels of LIPIN1, a PPARα co-activator, and of the protein that controls its levels and localization, hypoxia-inducible factor 1α (HIF-1α). These changes were prevented by lipid exposure through a mechanism that might involve a decrease in succinate levels. Finally, Sirt3−/− mice fed the HFD showed increased levels of some proteins involved in lipid uptake, such as CD36 and the VLDL receptor. The upregulation in CD36 was confirmed in Huh-7 cells treated with a SIRT3 inhibitor or transfected with SIRT3 siRNA and incubated with palmitate, an effect that was prevented by the Nrf2 inhibitor ML385. Conclusion These findings demonstrate new mechanisms by which Sirt3 deficiency contributes to hepatic steatosis. Graphical abstract

scholarly journals Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3610-3624 ◽  
Author(s):  
Gabriele Schoiswohl ◽  
Maja Stefanovic-Racic ◽  
Marie N. Menke ◽  
Rachel C. Wills ◽  
Beth A. Surlow ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Target Genes ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Peroxisome Proliferator ◽  
Immune Cell Infiltration ◽  
Lipid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Triacylglycerol Hydrolysis

Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocyte-specific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation, and expression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.

scholarly journals Estrogen-Related Receptor α Directs Peroxisome Proliferator-Activated Receptor α Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle

2004 ◽  
Vol 24 (20) ◽  
pp. 9079-9091 ◽  
Author(s):  
Janice M. Huss ◽  
Inés Pineda Torra ◽  
Bart Staels ◽  
Vincent Giguère ◽  
Daniel P. Kelly
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Target Genes ◽  
Cellular Fatty Acid ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Oxidation Rates

ABSTRACT Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERRα have not been well defined. To identify ERRα-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERRα. ERRα upregulated a subset of PGC-1α target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration. These results were validated by independent analyses in cardiac myocytes, C2C12 myotubes, and cardiac and skeletal muscle of ERRα−/− mice. Consistent with the gene expression results, ERRα increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERRα are known targets for the nuclear receptor PPARα, and therefore, the interaction between these regulatory pathways was explored. ERRα activated PPARα gene expression via direct binding of ERRα to the PPARα gene promoter. Furthermore, in fibroblasts null for PPARα and ERRα, the ability of ERRα to activate several PPARα targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1α was also shown to activate ERRα gene expression. We conclude that ERRα serves as a critical nodal point in the regulatory circuitry downstream of PGC-1α to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.

scholarly journals Characterization of the transactivation domain in the peroxisome-proliferator-activated receptor γ co-activator (PGC-1)

2007 ◽  
Vol 403 (3) ◽  
pp. 511-518 ◽  
Author(s):  
Prabodh Sadana ◽  
Edwards A. Park
Keyword(s):  
Transcriptional Activation ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Transactivation Domain ◽  
Peroxisome Proliferator Activated Receptor ◽  
N Terminus ◽  
Cpt I

The PGC-1s (peroxisome-proliferator-activated receptor γ co-activators) are a family of transcriptional regulators that induce the expression of various metabolic genes. PGC-1 proteins stimulate genes involved in mitochondrial biogenesis, fatty acid oxidation and hepatic gluconeogenesis. Previous studies have demonstrated that the PGC-1α and β isoforms interact with nuclear receptors through the conserved LXXLL (leucine-X-X-leucine-leucine) motifs. In the present study, we have investigated the mechanisms by which these PGC-1 isoforms stimulate gene expression. We have determined that the N-terminus of PGC-1 is responsible for transcriptional activation. Two conserved peptide motifs were identified in the N-terminus of PGC-1α and β isoforms. These domains were named AD1 and AD2 (activation domain 1 and 2). Deletion of both of these motifs decreased the induction of various PGC-1-regulated genes including the PEPCK (phosphoenolpyruvate carboxykinase) and CPT-I (carnitine palmitoyltransferase-I) genes. It was determined that amino acids containing a negative charge in AD1 and the leucine residues in AD2 were important for the transcriptional induction of the PEPCK and CPT-I genes. Disruption of the AD motifs did not diminish the ability of the PGC-1α protein to associate with the PEPCK or CPT-I genes. In addition, deletion of the AD domains did not eliminate the ability of PGC-1α to interact with the thyroid hormone receptor. The data indicate that the AD1 and AD2 motifs mediate the induction of many PGC-1- responsive genes, but they do not contribute to the recruitment of PGC-1 to target genes.

scholarly journals The Peroxisome Proliferator-Activated Receptor N-Terminal Domain Controls Isotype-Selective Gene Expression and Adipogenesis

2006 ◽  
Vol 20 (6) ◽  
pp. 1261-1275 ◽  
Author(s):  
Sarah Hummasti ◽  
Peter Tontonoz
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Target Genes ◽  
Biological Effects ◽  
Binding Domain ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
N Terminus

Abstract Peroxisome proliferator-activated receptors (PPARγ, PPARα, and PPARδ) are important regulators of lipid metabolism. Although they share significant structural similarity, the biological effects associated with each PPAR isotype are distinct. For example, PPARα and PPARδ regulate fatty acid catabolism, whereas PPARγ controls lipid storage and adipogenesis. The different functions of PPARs in vivo can be explained at least in part by the different tissue distributions of the three receptors. The question of whether the receptors have different intrinsic activities and regulate distinct target genes, however, has not been adequately explored. We have engineered cell lines that express comparable amounts of each receptor. Transcriptional profiling of these cells in the presence of selective agonists reveals partially overlapping but distinct patterns of gene regulation by the three PPARs. Moreover, analysis of chimeric receptors points to the N terminus of each receptor as the key determinant of isotype-selective gene expression. For example, the N terminus of PPARγ confers the ability to promote adipocyte differentiation when fused to the PPARδ DNA binding domain and ligand binding domain, whereas the N terminus of PPARδ leads to the inappropriate expression of fatty acid oxidation genes in differentiated adipocytes when fused to PPARγ. Finally, we demonstrate that the N terminus of each receptor functions in part to limit receptor activity because deletion of the N terminus leads to nonselective activation of target genes. A more detailed understanding of the mechanisms by which the individual PPARs differentially regulate gene expression should aid in the design of more effective drugs, including tissue- and target gene-selective PPAR modulators.

scholarly journals Leptin decreases BC cell susceptibility to NK lysis via PGC1A pathway

2020 ◽  
Vol 9 (6) ◽  
pp. 578-586
Author(s):  
Hichem Bouguerra ◽  
Gorrab Amal ◽  
Stephan Clavel ◽  
Hamouda Boussen ◽  
Jean-François Louet ◽  
...  
Keyword(s):  
Mrna Level ◽  
Hypoxia Inducible Factor ◽  
Tumor Development ◽  
Underlying Mechanism ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Tumor Escape ◽  
Tumor Resistance ◽  
Peroxisome Proliferator Activated Receptor ◽  
Potential Implication

Large prospective studies established a link between obesity and breast cancer (BC) development. Yet, the mechanisms underlying this association are not fully understood. Among the diverse adipocytokine secreted by hypertrophic adipose tissue, leptin is emerging as a key candidate molecule linking obesity and cancer, since it promotes proliferation and invasiveness of tumors. However, the potential implication of leptin on tumor escape mechanisms remains unknown. This study aims to explore the effect of leptin on tumor resistance to NK lysis and the underlying mechanism. We found that leptin promotes both BC resistance to NK92-mediated lysis and β oxidation on MCF-7, by the up-regulation of a master regulator of mitochondrial biogenesis, the peroxisome proliferator activated receptor coactivator-1 α (PGC1A). Using adenoviral approaches, we show that acute elevation of PGC1A enhances the fatty acid oxidation pathway and decreases the susceptibility of BC cells to NK92-mediated lysis. Importantly, we identified the involvement of PGC1A and leptin in the regulation of hypoxia inducible factor-1 alpha (HIF1A) expression by tumor cells. We further demonstrate that basal BC cells MDA-MB-231 and BT-20 exhibit an increased PGC1A mRNA level and an enhanced oxidative phosphorylation activity; in comparison with luminal BC cells MCF7 and MDA-361, which are associated with more resistance NK92 lysis. Altogether, our results demonstrate for the first time how leptin could promote tumor resistance to immune attacks. Reagents blocking leptin or PGC1A activity might aid in developing new therapeutic strategies to limit tumor development in obese BC patients.

scholarly journals PPARαin Obesity: Sex Difference and Estrogen Involvement

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-16 ◽  
Author(s):  
Michung Yoon
Keyword(s):  
Target Genes ◽  
Molecular Level ◽  
Body Weight Gain ◽  
Lipoprotein Metabolism ◽  
Lipid Lowering ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ovariectomized Mice ◽  
Hepatic Fatty Acid Oxidation

Peroxisome proliferator-activated receptorα(PPARα) is a member of the steroid hormone receptor superfamily and is well known to act as the molecular target for lipid-lowering drugs of the fibrate family. At the molecular level, PPARαregulates the transcription of a number of genes critical for lipid and lipoprotein metabolism. PPARαactivators are further shown to reduce body weight gain and adiposity, at least in part, due to the increase of hepatic fatty acid oxidation and the decrease in levels of circulating triglycerides responsible for adipose cell hypertrophy and hyperplasia. However, these effects of the PPARαligand fenofibrate on obesity are regulated with sexual dimorphism and seem to be influenced by the presence of functioning ovaries, suggesting the involvement of ovarian steroids in the control of obesity by PPARα. In female ovariectomized mice, 17β-estradiol inhibits the actions of fenofibrate on obesity through its suppressive effects on the expression of PPARαtarget genes, and these processes may be mediated by inhibiting the coactivator recruitment of PPARα. Thus, it is likely that PPARαfunctions on obesity may be enhanced in estrogen-deficient states.

scholarly journals Mouse trefoil factor 3 ameliorated high-fat-diet-induced hepatic steatosis via increasing peroxisome proliferator-activated receptor-α-mediated fatty acid oxidation

2019 ◽  
Vol 317 (3) ◽  
pp. E436-E445
Author(s):  
Xiaojie Wu ◽  
Hongze Zheng ◽  
Rui Yang ◽  
Xiying Luan ◽  
Lingyun Zhang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Marker Gene ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Trefoil Factor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Trefoil Factor 3

Hepatic trefoil factor 3 (Tff3) was identified as a potential protein for the treatment of diabetes, yet the effect of Tff3 on nonalcoholic fatty liver disease (NAFLD) has never been explored. Here, we found that the expression of hepatic Tff3 was significantly decreased in NAFLD mice models, suggesting that Tff3 was a potential marker gene for NAFLD. Restoring the expression of Tff3 in the liver of NAFLD mice, including diabetic (db), obese (ob/ob), and diet-induced obese mice, with adenovirus-mediated Tff3 ( Ad-Tff3) apparently attenuates the fatty liver phenotype. In contrast, adenovirus-mediated knockdown of Tff3 ( Ad-shTff3) in C57BL/6J mice results in an obvious fatty liver phenotype. Furthermore, our molecular experiments indicated that hepatic Tff3 could alleviate hepatic steatosis via upregulating the expression of peroxisome proliferator-activated receptor-α ( PPARα) directly, thereby enhancing the fatty acid oxidation process in the liver. Notably, we found that Tff3 attenuates the fatty liver phenotype independent of modulation of lipogenesis and improves the capacity of anti-inflammation. Overall, our results suggested that hepatic Tff3 could be effectively used as a potential therapy target for the treatment of NAFLD.

scholarly journals SIRT4 Represses Peroxisome Proliferator-Activated Receptor α Activity To Suppress Hepatic Fat Oxidation

2013 ◽  
Vol 33 (22) ◽  
pp. 4552-4561 ◽  
Author(s):  
Gaëlle Laurent ◽  
Vincent C. J. de Boer ◽  
Lydia W. S. Finley ◽  
Meredith Sweeney ◽  
Hong Lu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Oxidation ◽  
Target Genes ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Oxidation Rates ◽  
Hepatic Fat ◽  
Important Regulator

Sirtuins are a family of protein deacetylases, deacylases, and ADP-ribosyltransferases that regulate life span, control the onset of numerous age-associated diseases, and mediate metabolic homeostasis. We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability. We show that SIRT4 levels decrease in the liver during fasting and that SIRT4 null mice display increased expression of hepatic peroxisome proliferator-activated receptor α (PPARα) target genes associated with fatty acid catabolism. Accordingly, primary hepatocytes from SIRT4 knockout (KO) mice exhibit higher rates of fatty acid oxidation than wild-type hepatocytes, and SIRT4 overexpression decreases fatty acid oxidation rates. The enhanced fatty acid oxidation observed in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating a clear cross talk between mitochondrial and nuclear sirtuins. Thus, SIRT4 is a new component of mitochondrial signaling in the liver and functions as an important regulator of lipid metabolism.

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