scholarly journals Peroxisome proliferator-activated receptor α activation regulates lipid metabolism in the feto-placental unit from diabetic rats

Reproduction ◽  
2008 ◽  
Vol 136 (1) ◽  
pp. 95-103 ◽  
Author(s):  
N Martínez ◽  
E Capobianco ◽  
V White ◽  
M C Pustovrh ◽  
R Higa ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Maternal Diabetes ◽  
Diabetic Rats ◽  
Peroxisome Proliferator ◽  
Cholesteryl Esters ◽  
Placental Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Diabetic Placenta ◽  
Release Of Glycerol

Maternal diabetes promotes an overaccumulation of lipids in the feto-placental unit and impairs feto-placental development and growth. Here, we investigated the role played by the nuclear receptor peroxisome proliferator-activated receptor (PPAR)α in lipid metabolism in fetuses and placentas from control and neonatal streptozotocin-induced diabetic rats. Placentas and fetuses were studied on day 13.5 of gestation. The concentrations of PPARα (by Western blot) and its endogenous agonist leukotriene B4 (LTB4) (by enzyme immunoassay) were analysed. Placental explants and fetuses were cultured with LTB4 or clofibrate, and then lipid metabolism analysed (concentrations and synthesis from 14C-acetate of triglycerides, phospholipids, cholesterol and cholesteryl esters; release of glycerol and free fatty acids (FFAs)). We found that maternal diabetes led to increases in placental concentrations of triglycerides and cholesteryl esters, and fetal concentrations of phospholipids. PPARα agonists downregulated fetal and placental lipid concentrations in control and diabetic rats. The synthesis of lipids was reduced in the diabetic placenta but increased in fetuses from diabetic animals. PPARα agonists reduced the synthesis of lipids in control placenta and in the fetuses from control and diabetic rats. Glycerol and FFA release was enhanced in the diabetic placenta and in control placenta cultured with PPARα agonists. Maternal diabetes led to reductions in fetal and placental LTB4 concentrations and to increases in placental PPARα concentrations. Overall, these data support a novel role of PPARα as a regulator of lipid metabolism in the feto-placental unit, relevant in maternal diabetes where fetal and placental PPARα, LTB4 and lipid concentrations are altered.

Sirtuin 1 is involved in oleic acid-induced calf hepatocyte steatosis via alterations in lipid metabolism-related proteins

2021 ◽  
Vol 99 (10) ◽  
Author(s):  
Hongyan Ding ◽  
Yu Li ◽  
Leihong Liu ◽  
Ning Hao ◽  
Suping Zou ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Mrna Abundance ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Acetyl Coa Carboxylase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lower Protein ◽  
Tag Accumulation

Abstract Sirtuin 1 (SIRT1), an NAD-dependent protein deacetylase, plays a central role in the control of lipid metabolism in nonruminants. However, the role of SIRT1 in hepatic lipid metabolism in dairy cows with fatty liver is not well known. Thus, we used isolated primary bovine hepatocytes to determine the role of SIRT1 in protecting cells against oleic acid (OA)-induced steatosis. Recombinant adenoviruses to overexpress (AD-GFP-SIRT1-E) or knockdown (AD-GFP-SIRT1-N) SIRT1 were used for transduction of hepatocytes. Calf hepatocytes isolated from five female calves (1 d old, 30 to 40 kg) were used to determine both time required and the lowest dose of OA that could induce triacylglycerol (TAG) accumulation. Analyses indicated that 0.25 mM OA for 24 h was suitable to induce TAG accumulation. In addition, OA not only led to an increase in TAG, but also upregulated mRNA and protein abundance of sterol regulatory element-binding transcription factor 1 (SREBF1) and downregulated SIRT1 and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PPARGC1A). Thus, these in vitro conditions were deemed optimal for subsequent experiments. Calf hepatocytes were cultured and incubated with OA (0.25 mM) for 24 h, followed by adenoviral AD-GFP-SIRT1-E or AD-GFP-SIRT1-N transduction for 48 h. Overexpression of SIRT1 led to greater protein and mRNA abundance of SIRT1 along with fatty acid oxidation-related genes including PPARGC1A, peroxisome proliferator-activated receptor alpha (PPARA), retinoid X receptor α (RXRA), and ratio of phospho-acetyl-CoA carboxylase alpha (p-ACACA)/total acetyl-CoA carboxylase alpha (ACACA). In contrast, it resulted in lower protein and mRNA abundance of genes related to lipid synthesis including SREBF1, fatty acid synthase (FASN), apolipoprotein E (APOE), and low-density lipoprotein receptor (LDLR). The concentration of TAG decreased due to SIRT1 overexpression. In contrast, silencing SIRT1 led to lower protein and mRNA abundance of SIRT1, PPARGC1A, PPARA, RXRA, and greater protein and mRNA abundance of SREBF1, FASN, APOE, and LDLR. Further, those responses were accompanied by greater content of cellular TAG and total cholesterol (TC). Overall, data from these in vitro studies indicated that SIRT1 is involved in the regulation of lipid metabolism in calf hepatocytes subjected to an increase in the supply of OA. Thus, it is possible that alterations in SIRT1 abundance and activity in vivo contribute to development of fatty liver in dairy cows.

scholarly journals PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice

2020 ◽  
Vol 21 (6) ◽  
pp. 2061 ◽  
Author(s):  
Yaping Wang ◽  
Takero Nakajima ◽  
Frank J. Gonzalez ◽  
Naoki Tanaka
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Liver Cancer ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Regulators

Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer. PPARβ/δ promotes fatty acid β-oxidation largely in extrahepatic organs, and PPARγ stores triacylglycerol in adipocytes. Investigations using liver-specific PPAR-disrupted mice have revealed major but distinct contributions of the three PPARs in the liver. This review summarizes the findings of liver-specific PPAR-null mice and discusses the role of PPARs in the liver.

scholarly journals LRRK2 Regulates CPT1A to Promote β-Oxidation in HepG2 Cells

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4122 ◽  
Author(s):  
Chiao-Wei Lin ◽  
Yu-Ju Peng ◽  
Yuan-Yu Lin ◽  
Harry John Mersmann ◽  
Shih-Torng Ding
Keyword(s):  
Lipid Metabolism ◽  
Hepg2 Cells ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Α ◽  
Amp Activated Protein Kinase ◽  
Necrosis Factor

Leucine-rich repeat kinase 2 (LRRK2) is involved in lipid metabolism; however, the role of LRRK2 in lipid metabolism to affect non-alcoholic fatty liver disease (NAFLD) is still unclear. In the mouse model of NAFLD induced by a high-fat diet, we observed that LRRK2 was decreased in livers. In HepG2 cells, exposure to palmitic acid (PA) down-regulated LRRK2. Overexpression and knockdown of LRRK2 in HepG2 cells were performed to further investigate the roles of LRRK2 in lipid metabolism. Our results showed that β-oxidation in HepG2 cells was promoted by LRRK2 overexpression, whereas LRRK2 knockdown inhibited β-oxidation. The critical enzyme of β-oxidation, carnitine palmitoyltransferase 1A (CPT1A), was positively regulated by LRRK2. Our data suggested that the regulation of CPT1A by LRRK2 may be via the activation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). The overexpression of LRRK2 reduced the concentration of a pro-inflammatory cytokine, tumor necrosis factor α (TNFα), induced by PA. The increase in β-oxidation may promote lipid catabolism to suppress inflammation induced by PA. These results indicated that LRRK2 participated in the regulation of β-oxidation and suggested that the decreased LRRK2 may promote inflammation by suppressing β-oxidation in the liver.

scholarly journals New Transcriptional Reporters to Quantify and Monitor PPARγ Activity

PPAR Research ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Séverine A. Degrelle ◽  
Hussein Shoaito ◽  
Thierry Fournier
Keyword(s):  
Lipid Metabolism ◽  
Critical Role ◽  
Reporter Genes ◽  
Cell Types ◽  
Peroxisome Proliferator ◽  
Biological Processes ◽  
Placental Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Receptor Superfamily ◽  
Different Cell Types

The peroxisome-proliferator-activated-receptor-γ (PPARγ) is a member of the nuclear receptor superfamily that plays a critical role in diverse biological processes, including adipogenesis, lipid metabolism, and placental development. To study the activity of PPARγ, we constructed two new reporter genes: a fluorescent GFP-tagged histone-2B (PPRE-H2B-eGFP) and a secreted nanoluciferase (PPRE-pNL1.3[secNluc]). This study demonstrates their usage to monitor PPARγ activity in different cell types and screen for PPARγ’s potential ligands.

scholarly journals Preventing type 2 diabetes and cardiovascular disease in metabolic syndrome: the role of PPARα

2007 ◽  
Vol 4 (3_suppl) ◽  
pp. S12-S14 ◽  
Author(s):  
Jorge Plutzky
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Lipid Metabolism ◽  
Drug Target ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Central Target ◽  
The Metabolic Syndrome

The clustering of cardiovascular risk factors associated with the metabolic syndrome and type 2 diabetes suggests central mechanisms may exist that account for the presence of these abnormalities. Likewise, this clustering also suggests that key therapeutic targets may exist that could allow improvements in many of these parameters. Extensive data implicate peroxisome proliferator-activated receptor-alpha (PPARα) as an important transcriptional regulator of lipid metabolism, energy balance and inflammation. PPARα is also an established drug target. Experimental data show that activation of PPARα by agonists such as fenofibrate improves dyslipidaemia, increases cholesterol efflux and limits inflammation. All of these effects would also be predicted to decrease atherosclerotic risk. Evidence from surrogate markers in humans is also supportive of the concept that PPARα may act as a central target capable of influencing a variety of different pathways involved in lipid metabolism. Thus, fenofibrate offers the potential for inducing a co-ordinated PPARα response that may improve dyslipidaemia, repress inflammation and limit atherosclerosis in patients with the metabolic syndrome or type 2 diabetes.

scholarly journals Aberrant miR199a-5p/caveolin1/PPARα axis in hepatic steatosis

2014 ◽  
Vol 53 (3) ◽  
pp. 393-403 ◽  
Author(s):  
Bo Li ◽  
Zhiguo Zhang ◽  
Huizhi Zhang ◽  
Kai Quan ◽  
Yan Lu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Fatty Liver ◽  
Vital Role ◽  
Mitochondrial Activity ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Atp Levels ◽  
Excessive Accumulation

The prevalence of non-alcoholic fatty liver disease (NAFLD), a condition characterized by an excessive accumulation of triglycerides (TGs) in hepatocytes, has dramatically increased globally during recent decades. MicroRNAs (miRs) have been suggested to play crucial roles in many complex diseases and lipid metabolism. Our results indicated that miR199a-5p was remarkably upregulated in free fatty acid (FA)-treated hepatocytes. To investigate the role of miR199a-5p in the pathogenesis of fatty liver and the potential mechanism by which miR199a-5p regulates NAFLD, we first transfected two hepatocyte cell lines, HepG2 and AML12 cells, with agomiR199a-5p or antagomiR199a-5p. Our results indicated that miR199a-5p overexpression exacerbated deposition of FA and inhibited ATP levels and mitochondrial DNA (mtDNA) contents. Consistently, suppression of miR199a-5p partially alleviated deposition of FA and increased ATP levels and mtDNA contents. Moreover, miR199a-5p suppressed the expression of mitochondrial FA β-oxidation-related genes through inhibition of caveolin1 (CAV1) and the related peroxisome proliferator-activated receptor alpha (PPARα) pathway. Furthermore, suppression of CAV1 gene expression by CAV1 siRNA inhibited the PPARα signalling pathway. Finally, we examined the expression of miR199a-5p in liver samples derived from mice fed a high-fat diet, db/db mice, ob/ob mice and NAFLD patients, and found that miR199a-5p was upregulated while CAV1 and PPARA were downregulated in these systems, which was strongly indicative of the essential role of miR199a-5p in NAFLD. In summary, miR199a-5p plays a vital role in lipid metabolism, mitochondrial activity and mitochondrial β-oxidation in liver. Upregulated miR199a-5p in hepatocytes may contribute to impaired FA β-oxidation in mitochondria and aberrant lipid deposits, probably via CAV1 and the PPARα pathway.

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