Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms by which ethanol consumption causes accumulation of hepatic triacylglycerols are complex. AMP-activated protein kinase (AMPK) plays a central role in the regulation of lipid metabolism. Therefore, in the present study we investigated whether AMPK may have a role in the development of ethanol-induced fatty liver. Hepatocytes isolated from rats fed with an ethanol-containing liquid diet showed higher rates of fatty acid and triacylglycerol syntheses, but a decreased rate of fatty acid oxidation, concomitant to a lower activity of carnitine palmitoyltransferase I. Hepatocytes from both ethanol-fed and pair-fed control rats were incubated with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an AMPK activator in intact cells. In both hepatocyte preparations AICAR strongly inhibited the activity of acetyl-CoA carboxylase in parallel to fatty acid synthesis, but cells from ethanol-fed rats showed significantly lower sensitivity to inhibition by AICAR. Moreover, AICAR strongly decreased triacylglycerol synthesis and increased fatty acid oxidation in control hepatocytes, but these effects were markedly attenuated in hepatocytes from ethanol-fed rats. In parallel, AMPK in liver of ethanol-fed rats showed a decreased specific activity and a lower sensitivity to changes in the AMP/ATP ratio, compared to the enzyme of control rats. These effects are consistent with the impairment of AMPK-mediated regulation of fatty acid metabolism after ethanol consumption, that will facilitate triacylglycerol accumulation. Taken together, these findings suggest that a decreased AMPK activity may have an important role in the development of alcoholic fatty liver.
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PMID:Ethanol consumption impairs regulation of fatty acid metabolism by decreasing the activity of AMP-activated protein kinase in rat liver. 1799 5

Our previous study found that thyroid-stimulating hormone promoted sterol regulatory element-binding protein-2 (SREBP-2) expression and suppressed AMP-activated protein kinase (AMPK) activity in the liver, but it was unclear whether there was a direct link between TSH, AMPK and SREBP-2. Here, we demonstrate that the 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-induced activation of AMPK directly inhibited the expression of SREBP-2 and its target genes HMGCR and HMGCS, which are key enzymes in cholesterol biosynthesis, and suppressed the TSH-stimulated up-regulation of SREBP-2 in HepG2 cells; similar results were obtained in TSH receptor knockout mice. Furthermore, AMPK, an evolutionally conserved serine/threonine kinase, phosphorylated threonine residues in the precursor and nuclear forms of SREBP-2, and TSH interacted with AMPK to influence SREBP-2 phosphorylation. These findings may represent a molecular mechanism by which AMPK ameliorates the hepatic steatosis and hypercholesterolemia associated with high TSH levels in patients with subclinical hypothyroidism (SCH).
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PMID:AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver. 2593 5

The thyroid hormone responsive spot 14 (THRSP) gene is a de novo lipogenesis-related gene that plays a significant role in the initiation and development of nonalcoholic fatty liver disease (NAFLD). Several previous studies had shown that endogenous and environmental factors could regulate the expression of THRSP. The role of microRNAs (miRNAs), however, in controlling THRSP expression has not been investigated. In this study, we first constructed the hepatic steatosis cell model by using a mixture of free fatty acids (FFAs; oleate/palmitate, 2:1 ratio) to treat and demonstrate the promotive role of THRSP in lipid accumulation in hepatic cells. By analyzing the photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) database and performing a luciferase reporter assay, we confirmed that microRNA-451a specifically binds to mouse and human THRSP 3'UTR and inhibits its activity. Overexpression of miR-451a efficiently reduced THRSP mRNA and protein expression as well as triglyceride (TG) accumulation in cultured hepatic cells (AML12 and HepG2). Moreover, overexpression of miR-451a significantly decreases TG accumulation in the livers of mice injected with an miR-451a agomir. All these results demonstrated that miR-451a might participate in the FFA-induced hepatic steatosis by regulating the expression of the THRSP gene which represents a new potential target for NAFLD therapy.
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PMID:MiR-451a attenuates free fatty acids-mediated hepatocyte steatosis by targeting the thyroid hormone responsive spot 14 gene. 2960 29