Regulation of hepatic lipid metabolism

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AMPK phosphorylates and inactivates a number of metabolic enzymes involved in lipid metabolism in order to maintain liver energy status. AMPK coordinates the changes in the hepatic lipid metabolism and, so, regulates the partitioning of fatty acids between oxidative and biosynthetic pathways. 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and acetyl CoA carboxylase (ACC), key enzymes in cholesterol and fatty acid synthesis respectively, were the first enzymes shown to be phosphorylated and inactivated by AMPK (Corton et al., 1994, Henin et al., 1995). Although the action of AMPK is achieved by rapid and direct phosphorylation of these enzymes, long-term effects have also been clearly demonstrated on gene expression. AMPK activation by AICAR or by the use of adenovirus-mediated overexpression of a constitutively active form of the a2 catalytic subunit (AMPKa2-CA) inhibits glycolytic and lipogenic gene expression (Foretz et al., 2005, Leclerc et al., 2001, Woods et al., 2000, Foretz et al., 1998, Leclerc et al., 1998), preserving glucose for ATP-producing pathways rather than for lipid synthesis. Of note, AMPK activation reduces expression of sterol regulatory element-binding protein-1c (SREBP1c) (Zhou et al., 2001, Foretz et al., 2005) and carbohydrate response element–binding protein (ChREBP) (Foretz et al., 2005, Kawaguchi et al., 2002), transcription factors playing a key role in the transcriptional regulation of lipogenic and glycolytic genes by insulin and glucose, respectively. In addition, it has been also reported that AMPK directly phosphorylates ChREBP and modulates its DNA binding activity (Kawaguchi et al., 2002). Polyunsaturated fatty acids (PUFAs) are known to repress glycolytic and lipogenic gene expression and raised the question about a role of AMPK in mediating the effect of PUFAs on gene transcription. To address this point, we investigated the effect of PUFAs in mice lacking AMPKa1/a2 catalytic subunits in the liver (AMPKa1a2_LS-/-). In the absence of hepatic AMPK, PUFAs continue to inhibit glycolytic and lipogenic gene expression indicating the existence of AMPK-independent mechanism(s) (Viollet et al., 2006).

In the cholesterol synthesis pathway, AMPK blocks the conversion of HMG-CoA to mevalonate. One could expect detrimental effect on cholesterol homeostasis when AMPK activity is altered. In total and liver-specific AMPKa2 KO mice, plasma levels for total and HDL cholesterol are not statistically different compared to controls but have a tendency to be higher (Andreelli et al., 2006, Viollet et al., 2003). This suggested that remaining a1 subunit activity in AMPKa2 KO mice is sufficient to control hepatic cholesterol synthesis and that HMG-CoA reductase is a target for both catalytic isoforms of AMPK.

ACC is an important rate-controlling enzyme for the synthesis of malonyl-CoA, which is both a critical precursor for biosynthesis of fatty acids and a potent inhibitor of mitochondrial fatty acid oxidation via the allosteric regulation of carnitine palmitoyltransferase-1 (CPT-1) which catalyzes the entry of long-chain fatty acyl-CoA into mitochondria. Inhibition of ACC by AMPK leads to a fall in malonyl-CoA content and a subsequent decrease in fatty acid synthesis concomitantly with an increase in b-oxidation (Brusq et al., 2006, Velasco et al., 1997). Exposure of hepatocytes to AICAR also produces a strong stimulation of long-chain fatty acid oxidation as a result of an increase in the rate of ketogenesis and an inhibition of triacylglycerol synthesis via phosphorylation of sn-glycerol-3-phosphate acyltransferase (GPAT) (Muoio et al., 1999). In addition, overexpression of AMPKa2-CA in the liver increases plasma ketone bodies levels, a surrogate marker for hepatic b-oxidation (Foretz et al., 2005). Interestingly, AMPK-induced ACC phosphorylation is impaired in hepatocytes deleted of both catalytic subunit, contributing to increase intracellular malonyl CoA levels and triglyceride (TG) accumulation in the liver (B. Viollet, M. Foretz, unpublished results). Thus, these results indicate that AMPK regulates cellular lipid metabolism in large part through stimulation of fatty acid oxidation. However, recent studies showed that AMPK also stimulates a previously unrecognized pathway that involves constitutive exocytosis of lipoproteins (Puljak et al., 2008). This alternative pathway appears to be quantitatively important for intracellular lipid homeostasis and may function in parallel with fatty acid oxidation to regulate intracellular lipid content.