Moreover, a lysine acetylation/deacetylation-sumoylation switch has been implicated in the functional regulation of several important molecules.22, 23 Ethanol inhibits sirtuin 1 (SIRT1), an nicotinamide adenine dinucleotide-positive–-dependent class III protein deacetylase, both in cultured hepatic cells and in animals.13, 24 It is possible that this ethanol-mediated hyperacetylation/hyposumoylation of lipin-1 may be a consequence of the inhibition of SIRT1 by ethanol. Whether acetylation/sumoylation would serve as a molecular switch to control the nuclear localization and coactivator activity of lipin-1 in the liver and how ethanol affects the functional relationship of SIRT1 and lipin-1

Liproxstatin-1 price are currently under investigation in our laboratory. Lipin-1 localizes to the nucleus and is a component of a transcriptional complex with PPARα/PGC-1α, which stimulates fatty acid oxidation in the liver.3 Ethanol-mediated dysregulation of the hepatic PPARα/PGC-1α axis and subsequent incomplete stimulation of PPARα/PGC-1α target genes involved in fatty acid oxidation contributes to the development of alcoholic liver steatosis.17 Taken together with a recent study demonstrating that a high-fat-diet–induced fatty liver

is partially mediated by impairment of the PGC-1α/nuclear lipin-1/PPARα axis and fatty acid oxidation in mice, our current findings suggest that depletion of nuclear lipin-1 is likely to lead to impairment of the buy RO4929097 PPARα/PGC-1α axis and fatty acid oxidation in the livers of chronically ethanol-fed animals.25 Furthermore, lipin-1 subcellular localization regulates SREBP-1 signaling and selleck kinase inhibitor governs the

assembly and secretion of very-low-density lipoproteins (VLDLs).1, 4 It is tempting to speculate that ethanol-induced nucleocytoplasmic shuttling may activate SREBP-1 and impair VLDL secretion and, subsequently, contribute to hepatic fat accumulation. Another major novel finding of the present study is that ethanol up-regulates lipin-1 largely through inhibition of AMPK and activation of SREBP-1. Our study provides evidence, for the first time, to our knowledge, that AMPK is involved in the regulation of lipin-1 gene expression. However, the exact mechanism by which AMPK inhibition by ethanol leads to activation of SREBP-1, and subsequent inhibition of Lpin1, remains to be determined. Our earlier work showed that ethanol selectively increases hepatic SREBP-1 activity in rodent models through inhibition of AMPK.6, 9 AMPK directly phosphorylates SREBP-1 and suppresses SREBP-1 activity in hepatocytes exposed to high glucose.26 Conceivably, ethanol-mediated inhibition of AMPK may cause reduced phosphorylation of SREBP-1, which, in turn, results in activation of proteolytic processing and transcriptional activity of SREBP-1 and, ultimately, increased lipin-1 gene expression. Moreover, several lines of evidence have suggested functional connections between SIRT1 and AMPK.