Impact of maternal undernutrition around the time of conception on factors regulating hepatic lipid metabolism and microRNAs in singleton and twin fetuses

We have investigated the effects of embryo number and maternal undernutrition imposed either around the time of conception or before implantation on hepatic lipid metabolism in the sheep fetus. We have demonstrated that periconceptional undernutrition and preimplantation undernutrition each resulted in decreased hepatic fatty acid β-oxidation regulators, PGC-1α ( P < 0.05), PDK2 ( P < 0.01), and PDK4 ( P < 0.01) mRNA expression in singleton and twin fetuses at 135–138 days gestation. In singletons, there was also lower hepatic PDK4 ( P < 0.01), CPT-1 ( P < 0.01), and PKCζ ( P < 0.01) protein abundance in the PCUN and PIUN groups and a lower protein abundance of PDPK-1 ( P < 0.05) in the PCUN group. Interestingly, in twins, the hepatic protein abundance of p-AMPK (Ser485) ( P < 0.01), p-PDPK-1 (Ser41) ( P < 0.05), and PKCζ ( P < 0.05) was higher in the PCUN and PIUN groups, and hepatic PDK4 ( P < 0.001) and CPT-1 ( P < 0.05) protein abundance was also higher in the PIUN twin fetus. We also found that the expression of a number of microRNAs was altered in response to PCUN or PIUN and that there is evidence that these changes may underlie the changes in the protein abundance of key regulators of hepatic fatty acid β-oxidation in the PCUN and PIUN groups. Therefore, embryo number and the timing of maternal undernutrition in early pregnancy have a differential impact on hepatic microRNA expression and on the factors that regulate hepatic fatty acid oxidation and lipid synthesis.

Download Full-text

Perilipin 5 S155 phosphorylation by PKA is required for the control of hepatic lipid metabolism and glycemic control

The Journal of Lipid Research ◽

10.1194/jlr.ra120001126 ◽

2020 ◽

pp. jlr.RA120001126

Author(s):

Stacey N Keenan ◽

William DeNardo ◽

Jieqiong Lou ◽

Ralf B. Schittenhelm ◽

Magdalene K. Montgomery ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Glycemic Control ◽

Fatty Acid Oxidation ◽

Lipid Droplet ◽

Critical Role ◽

The Body ◽

Acid Oxidation ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid

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

Download Full-text

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.

Download Full-text

Glucagon-induced extracellular cAMP regulates hepatic lipid metabolism

Journal of Endocrinology ◽

10.1530/joe-16-0649 ◽

2017 ◽

Vol 234 (2) ◽

pp. 73-87 ◽

Cited By ~ 8

Author(s):

Sihan Lv ◽

Xinchen Qiu ◽

Jian Li ◽

Jinye Liang ◽

Weida Li ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Hepatic Steatosis ◽

Fatty Acid Oxidation ◽

Lipid Homeostasis ◽

Acid Oxidation ◽

Intracellular Camp ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Extracellular Camp

Hormonal signals help to maintain glucose and lipid homeostasis in the liver during the periods of fasting. Glucagon, a pancreas-derived hormone induced by fasting, promotes gluconeogenesis through induction of intracellular cAMP production. Glucagon also stimulates hepatic fatty acid oxidation but the underlying mechanism is poorly characterized. Here we report that following the acute induction of gluconeogenic genes Glucose 6 phosphatase (G6Pase) and Phosphoenolpyruvate carboxykinase (Pepck) expression through cAMP-response element-binding protein (CREB), glucagon triggers a second delayed phase of fatty acid oxidation genes Acyl-coenzyme A oxidase (Aox) and Carnitine palmitoyltransferase 1a (Cpt1a) expression via extracellular cAMP. Increase in extracellular cAMP promotes PPARα activity through direct phosphorylation by AMP-activated protein kinase (AMPK), while inhibition of cAMP efflux greatly attenuates Aox and Cpt1a expression. Importantly, cAMP injection improves lipid homeostasis in fasted mice and obese mice, while inhibition of cAMP efflux deteriorates hepatic steatosis in fasted mice. Collectively, our results demonstrate the vital role of glucagon-stimulated extracellular cAMP in the regulation of hepatic lipid metabolism through AMPK-mediated PPARα activation. Therefore, strategies to improve cAMP efflux could serve as potential new tools to prevent obesity-associated hepatic steatosis.

Download Full-text

Alcohol effects on hepatic lipid metabolism

The Journal of Lipid Research ◽

10.1194/jlr.r119000547 ◽

2020 ◽

Vol 61 (4) ◽

pp. 470-479 ◽

Cited By ~ 7

Author(s):

Sookyoung Jeon ◽

Rotonya Carr

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Hepatic Steatosis ◽

De Novo ◽

Lipid Synthesis ◽

Acid Oxidation ◽

Lipid Uptake ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation

Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease with significant morbidity and mortality worldwide. ALD begins with simple hepatic steatosis and progresses to alcoholic steatohepatitis, fibrosis, and cirrhosis. The severity of hepatic steatosis is highly associated with the development of later stages of ALD. This review explores the disturbances of alcohol-induced hepatic lipid metabolism through altered hepatic lipid uptake, de novo lipid synthesis, fatty acid oxidation, hepatic lipid export, and lipid droplet formation and catabolism. In addition, we review emerging data on the contributions of genetics and bioactive lipid metabolism in alcohol-induced hepatic lipid accumulation.

Download Full-text

Hepatic lipid metabolism in experimental nephrosis: decreased fatty acid oxidation and increased phosphatidate phosphohydrolase activity might contribute to the hyperlipidemia of the nephrotic syndrome

Atherosclerosis ◽

10.1016/0021-9150(94)93523-8 ◽

1994 ◽

Vol 109 (1-2) ◽

pp. 128

Author(s):

A. Al-Shurbaji ◽

D. Asiedu ◽

E. Humble ◽

M. Rudling ◽

R.K. Berge ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Phosphatidate Phosphohydrolase ◽

Experimental Nephrosis

Download Full-text

Atypical antipsychotic drugs perturb AMPK-dependent regulation of hepatic lipid metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00502.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. E624-E632 ◽

Cited By ~ 32

Author(s):

Kyoung-Jin Oh ◽

Jinyoung Park ◽

Su Yeon Lee ◽

Injae Hwang ◽

Jae Bum Kim ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Oxidation ◽

Transcriptional Activity ◽

Antipsychotic Drugs ◽

Acid Oxidation ◽

Phosphorylation Sites ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Ampk Activity

Dysregulation of lipid metabolism is a key feature of metabolic disorder related to side effects of antipsychotic drugs. Here, we investigated the molecular mechanism by which second-generation atypical antipsychotic drugs (AAPDs) affect hepatic lipid metabolism in liver. AAPDs augmented hepatic lipid accumulation by activating expression of sterol regulatory element-binding protein (SREBP) transcription factors, with subsequent induction of downstream target genes involved in lipid and cholesterol synthesis in hepatocytes. We confirmed the direct involvement of SREBPs on AAPD-induced expression of lipogenic and cholesterogenic genes by utilization of adenovirus for dominant negative SREBP (Ad-SREBP-DN). Interestingly, AAPDs significantly decreased phosphorylation of AMPKα and expression of fatty acid oxidation genes. Treatment of constitutive active AMPK restored AAPD-mediated dysregulation of genes involved in both lipid synthesis and fatty acid oxidation. Moreover, AAPDs decreased transcriptional activity of PPARα, a critical transcriptional regulator for controlling hepatic fatty acid oxidation, via an AMPK-dependent manner. Close investigations revealed that mutations at the known p38 MAPK phosphorylation sites (S6/12/21A), but not mutations at the putative AMPKα phosphorylation sites (S167/373/453A), block AAPD-dependent reduction of PPARα transcriptional activity, suggesting that p38 MAPK might be also involved in the regulatory pathway as a downstream effector of AAPDs/AMPK. Taken together, these data suggest that AAPD-stimulated hepatic dysregulation of lipid metabolism could result from the inhibition of AMPK activity, and pharmaceutical means to potentiate AMPK activity would contribute to restore hepatic lipid homeostasis that occurs during AAPD treatment.

Download Full-text