Dietary supplementation with soy isoflavones or replacement with soy proteins prevents hepatic lipid droplet accumulation and alters expression of genes involved in lipid metabolism in rats

Perilipin (PLIN) 5 is a lipid droplet-associated protein that coordinates intracellular lipolysis in highly oxidative tissues and is thought to regulate lipid metabolism in response to phosphorylation by protein kinase A (PKA). We sought to identify PKA phosphorylation sites in PLIN5 and assess their functional relevance in cultured cells and the livers of mice. We detected phosphorylation on S155, S161 and S163 of recombinant PLIN5 by PKA in vitro and identified S155 as a functionally important site for lipid metabolism. Expression of phosphorylation-defective PLIN5 S155A in Plin5 null cells resulted in decreased rates of lipolysis and triglyceride-derived fatty acid oxidation compared with cells expressing wildtype PLIN5. These differences in lipid metabolism were not associated with differences in the cellular distribution of PLIN5. Rather, FLIM-FRET analysis of protein-protein interactions showed that PLIN5 S155 phosphorylation regulates PLIN5 interaction with adipose triglyceride lipase (ATGL) at the lipid droplet, but not with the co-activator of ATGL, α-β hydrolase domain-containing 5 (ABHD5). Re-expression of PLIN5 S155A in the liver of Plin5 liver-specific null mice reduced lipolysis when compared to mice with wildtype PLIN5 re-expression, but was not associated with other changes in hepatic lipid metabolism, such as fatty acid oxidation, de novo lipogenesis and triglyceride secretion. Furthermore, glycemic control was impaired in mice with expression of PLIN5 S155A compared with mice expressing PLIN5. Together, these studies demonstrate that PLIN5 S155 is required for PKA-mediated lipolysis and builds on the body of evidence demonstrating a critical role for PLIN5 in coordinating lipid and glucose metabolism

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CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPKα2-SIRT1-PPARα signaling pathway

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.012543 ◽

2020 ◽

Vol 295 (50) ◽

pp. 17310-17322

Author(s):

Yann Deleye ◽

Alexia Karen Cotte ◽

Sarah Anissa Hannou ◽

Nathalie Hennuyer ◽

Lucie Bernard ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Oxidation ◽

Lipid Droplet ◽

Acid Oxidation ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Hepatic Fatty Acid Oxidation

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo. Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.

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Moringa Leaves Prevent Hepatic Lipid Accumulation and Inflammation in Guinea Pigs by Reducing the Expression of Genes Involved in Lipid Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms18071330 ◽

2017 ◽

Vol 18 (7) ◽

pp. 1330 ◽

Cited By ~ 17

Author(s):

Manal Almatrafi ◽

Marcela Vergara-Jimenez ◽

Ana Murillo ◽

Gregory Norris ◽

Christopher Blesso ◽

...

Keyword(s):

Lipid Metabolism ◽

Lipid Accumulation ◽

Guinea Pigs ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

Expression Of Genes

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Electronegative LDL promotes triglyceride-enriched lipid droplet accumulation in macrophages by inducing the expression of genes related to lipid metabolism

Atherosclerosis ◽

10.1016/j.atherosclerosis.2020.10.493 ◽

2020 ◽

Vol 315 ◽

pp. e159

Author(s):

S. Benitez ◽

N. Puig ◽

L. Montolio ◽

L. Navarra ◽

P. Camps-Renom ◽

...

Keyword(s):

Lipid Metabolism ◽

Lipid Droplet ◽

Expression Of Genes ◽

Electronegative Ldl

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Impact of dietary precursor ALA versus preformed DHA on fatty acid profiles of eggs, liver and adipose tissue and expression of genes associated with hepatic lipid metabolism in laying hens

Prostaglandins Leukotrienes and Essential Fatty Acids ◽

10.1016/j.plefa.2017.01.010 ◽

2017 ◽

Vol 119 ◽

pp. 1-17 ◽

Cited By ~ 8

Author(s):

M. Neijat ◽

P. Eck ◽

J.D. House

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Lipid Metabolism ◽

Laying Hens ◽

Fatty Acid Profiles ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Expression Of Genes

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Supplementing conjugated linoleic acid (CLA) in breeder hens diet increased CLA incorporation in liver and alters hepatic lipid metabolism in chick offspring

British Journal Of Nutrition ◽

10.1017/s0007114521000763 ◽

2021 ◽

pp. 1-41

Author(s):

Chun-Yan Fu ◽

Yan Zhang ◽

Wen-Bin Wang ◽

Xiang-Fa Wei ◽

Pei-Pei Yan ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Linoleic Acid ◽

Conjugated Linoleic Acid ◽

Fatty Acid Synthase ◽

Serum Triglyceride ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Breeder Hens ◽

Expression Of Genes

Abstract This experiment was designed to investigate the effect of supplementing conjugated linoleic acid (CLA) in breeder hens diet on development and hepatic lipid metabolism of chick offspring. Hy-Line Brown breeder hens were allocated into two groups, supplemented with 0 (CT) or 0.5% CLA for 8 weeks. Offspring chicks were grouped according to the mother generation and fed for 7 days. CLA treatment had no significant influence on development, egg quality, and fertility of breeder hens, but darkened the egg yolks in shade and increased yolk sac mass compared to CT group. Addition of CLA resulted in increased body mass and liver mass, and decreased deposition of subcutaneous adipose tissue in chick offspring. The serum triglyceride (TG) and cholesterol (TC) levels of chick offspring were decreased in CLA group. CLA treatment increased the incorporation of both CLA isomers (c9t11 and t10c12) in liver of chick offspring, accompanied by the decreased hepatic TG levels, related to the significant reduction of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) enzyme activities and the increased of carnitine palmitoyltransferase-1 (CPT1) enzyme activity. Meanwhile, CLA treatment reduced the mRNA expression of genes related to fatty acid biosynthesis (FAS, ACC, and sterol regulatory element-binding protein-1c), and induced the expression of genes related to β-oxidative (CPT1, AMP-activated protein kinase, and peroxisome proliferator-activated receptor α) in chick offspring liver. In summary, the addition of CLA in breeder hens diet significantly increased incorporation of CLA in liver of chick offspring, which further regulate hepatic lipid metabolism.

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Multifaceted regulation of hepatic lipid metabolism by YY1

Life Science Alliance ◽

10.26508/lsa.202000928 ◽

2021 ◽

Vol 4 (7) ◽

pp. e202000928

Author(s):

Gang Pan ◽

Klev Diamanti ◽

Marco Cavalli ◽

Ariadna Lara Gutiérrez ◽

Jan Komorowski ◽

...

Keyword(s):

Transcription Factors ◽

Lipid Metabolism ◽

Rna Sequencing ◽

Hepg2 Cells ◽

Liver Diseases ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Expression Of Genes ◽

Rigid Set ◽

Control Samples

Recent studies suggested that dysregulated YY1 plays a pivotal role in many liver diseases. To obtain a detailed view of genes and pathways regulated by YY1 in the liver, we carried out RNA sequencing in HepG2 cells after YY1 knockdown. A rigid set of 2,081 differentially expressed genes was identified by comparing the YY1-knockdown samples (n = 8) with the control samples (n = 14). YY1 knockdown significantly decreased the expression of several key transcription factors and their coactivators in lipid metabolism. This is illustrated by YY1 regulating PPARA expression through binding to its promoter and enhancer regions. Our study further suggest that down-regulation of the key transcription factors together with YY1 knockdown significantly decreased the cooperation between YY1 and these transcription factors at various regulatory regions, which are important in regulating the expression of genes in hepatic lipid metabolism. This was supported by the finding that the expression of SCD and ELOVL6, encoding key enzymes in lipogenesis, were regulated by the cooperation between YY1 and PPARA/RXRA complex over their promoters.

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