Management of fatty liver and hepatic fibrosis

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Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in western countries, is considered as the hepatic manifestation of the metabolic syndrome (Angulo, 2002). NAFLD is highly associated with obesity and insulin resistance and represent a broad spectrum of liver abnormalities ranging from simple hepatic steatosis (accumulation of TG inside hepatocytes) to a more severe form, nonalcoholic steatohepatitis (NASH), which is associated with hepatocyte damage, chronic inflammation, and fibrosis, and may progress to cirrhosis and liver failure. Studies in humans and various animal models have suggested that efforts to enhance insulin sensitivity might improve fatty liver disease, a situation frequently observed in patients with metabolic syndrome. The efficacy of metformin as a treatment for fatty liver disease has been confirmed in obese, ob/ob mice, which develop hyperinsulinemia, insulin resistance and fatty livers (Lin et al., 2000). Recent studies suggest that activation of AMPK accounts for the lipid-lowering effect of metformin in cultured hepatocytes (Zang et al., 2004). Similarly, adiponectin restores insulin sensitivity and decreases hepatic steatosis by lowering TG content in the liver of obese mice (Xu et al., 2003, Yamauchi et al., 2001). The action of adiponectin is linked to an activation of hepatic AMPK, ultimately leading to decreased fatty acid biosynthesis and increased mitochondrial fatty acid oxidation (Yamauchi et al., 2002). The role of AMPK has been confirmed by the decrease in liver TG content in lean and obese rodents during AICAR infusion (Bergeron et al., 2001) and treatment with direct AMPK activator A-769662 (Cool et al., 2006). In addition, it has been recently demonstrated that resveratrol improves insulin sensitivity and protects against lipid accumulation in the liver of diabetic and high-fat fed animals concomitantly with activation of hepatic AMPK (Baur et al., 2006, Shang et al., 2008). These effects have been correlated to increased mitochondrial number and SIRT1-mediated PCG-1a deacetylation, and decreased expression of lipogenic genes in the liver. Similarly, the beneficial effect of betaine (trimethylglycine), a naturally occurring metabolite of choline, on high-sucrose diet-induced hepatic steatosis in mice is associated with increased activation of hepatic AMPK (Song et al., 2007). Promising therapeutic effects of betaine supplementation on human NAFLD have been reported in a pilot clinical studies (Abdelmalek et al., 2001) but the use of betaine has been also described earlier in the treatment of alcoholic fatty liver disease (AFLD) (Barak et al., 1997). Although, the underlying causes of NAFLD and AFLD are clearly different, there are similarities in the disturbances of hepatic metabolism. This is supported by reports showing that treatement with adiponectin alleviated alcoholic and non-alcoholic fatty liver disease in mice, partly due to enhanced hepatic fatty acid oxidation and decreased fatty acid synthesis (Xu et al., 2003). Interestingly, chronic ethanol ingestion causes the impairment of AMPK-mediated regulation of fatty acid metabolism and may have an important role in the development of alcoholic fatty liver (You et al., 2004, Garcia-Villafranca et al., 2008). Activation of AMPK by AICAR or metformin largely blocked the ability of ethanol to increase levels of SREBP1c protein and expression of SREBP1c-regulated lipogenic enzymes and also appears to protect the liver from fatty changes associated with chronic alcohol use (You et al., 2004, Tomita et al., 2005). Very recently, treatment with resveratrol has been also shown to prevent the development of alcoholic liver steatosis through the SIRT1-AMPK signaling system associated with increased circulating adiponectin levels and enhanced expression of hepatic AdipoR1 and R2 receptors (Ajmo et al., 2008).

It is now established that hepatic stellate cells (HSCs) play a crucial role in the fibrotic response during the progression of NASH (Bataller and Brenner, 2005, Friedman, 2004). Stimuli such as liver injury activate and transdifferentiate HSCs from vitamin A-storing pericytes to myofibroblast-like cells. Once activated, human HSCs become proliferative, proinflammatory and profibrogenic through increased responsiveness to several soluble mediators (Friedman, 2004). Despite the clear role of insulin resistance in the progression of fibrosis, the molecular mechanisms involved in these conditions are still unclear. Adiponectin levels which have been directly correlated with insulin sensitivity are closely and inversely associated with degree of hepatic steatosis, necroinflammation, and fibrosis in NAFLD (Targher et al., 2006). Recent studies have demonstrated that in rat HSCs, adiponectin inhibits proliferation, migration, and expression of fibrogenic genes, and it may induce apoptosis of activated cells (Ding et al., 2005). Furthermore, in vivo administration of adiponectin prevents proliferation of activated HSCs and reduces the development of fibrosis and liver damage during experimental steatohepatitis (Xu et al., 2003, Kamada et al., 2003). In addition to adiponectin, AICAR and metformin significantly inhibited proliferation and migration of human HSCs in a dose-dependent manner (Caligiuri et al., 2008). The beneficial effect of these compounds is linked to suppression of platelet-derived growth factor (PDGF) expression in HSCs and subsequent inhibition of type I procollagen secretion (Caligiuri et al., 2008, Adachi and Brenner, 2008). Activation of AMPK by adiponectin plays a pivotal role in this molecular pathway since the dose-dependent PDGF suppression is abrogated in the presence of dominant-negative AMPK (Adachi and Brenner, 2008) or by the knock-down of AMPK (Caligiuri et al., 2008). Additional mechanisms, such as short-term inhibition of PDGF-mediated phosphorylation of ribosomal S6 kinase (p70S6K) and 4E binding protein-1 (4EBP1) (downstream effectors of the mammalian target of rapamycin complex 1 (mTORC1) pathway) by AICAR have been demonstrated (Caligiuri et al., 2008). AICAR and metformin could also inhibit HSCs proliferation via suppression of ROS production and subsequent inhibition of AKT pathway (Adachi and Brenner, 2008). Taken together, data from recent studies provide evidence that AMPK and adiponectin inhibit HSCs proliferation and hepatic fibrosis via multiple molecular mechanisms and suggest that use of drugs activating hepatic AMPK may have an additional rationale in their antifibrogenic properties