Involvement of Adiponectin-SIRT1-Ampk Signaling in the Protective Action of Rosiglitazone Against Alcoholic Fatty Liver in Mice

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lipid metabolism, signal transduction, transcriptional regulators, acetylation

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The development of alcoholic fatty liver is associated with reduced adipocyte-derived adiponectin levels, decreased hepatic adiponectin receptors, and deranged hepatic adiponectin signaling in animals. Peroxisomal proliferator-activated receptor-γ (PPAR-γ) plays a key role in the regulation of adiponectin in adipose tissue. The aim of the present study was to test the ability of rosiglitazone, a known PPAR-γ agonist, to reverse the inhibitory effects of ethanol on adiponectin expression and its hepatic signaling, and to attenuate alcoholic liver steatosis in mice. Mice were fed modified Lieber-DeCarli ethanol-containing liquid diets for 4 wk or pair-fed control diets. Four groups of mice were given a dose of either 3 or 10 mg·kg body wt−1·day−1 of rosiglitazone with or without ethanol in their diets for the last 2 wk of the feeding study. Coadministration of rosiglitazone and ethanol increased the expression and circulating levels of adiponectin and enhanced the expression of hepatic adiponectin receptors (AdipoRs) in mice. These increases correlated closely with the activation of a hepatic sirtuin 1 (SIRT1)-AMP-activated kinase (AMPK) signaling system. In concordance with stimulated SIRT1-AMPK signaling, rosiglitazone administration enhanced expression of fatty acid oxidation enzymes, normalized lipin 1 expression, and blocked elevated expression of genes encoding lipogenic enzymes which, in turn, led to increased fatty acid oxidation, reduced lipogenesis, and alleviation of steatosis in the livers of ethanol-fed mice. Enhanced hepatic adiponectin-SIRT1-AMPK signaling contributes, at least in part, to the protective action of rosiglitazone against alcoholic fatty liver in mice.

alcoholic fatty liver disease is one of the earliest and most common consequences of chronic and excess alcohol consumption and can lead to more severe forms of liver injury such as steatohepatitis, hepatic fibrosis, and cirrhosis in humans (27, 40). Therefore, the development of effective therapeutic strategies for alcoholic fatty liver is vital. In recent years, several novel mechanisms involved in the development of alcoholic fatty liver have emerged, providing crucial therapeutic leads (27, 40). Chronic ethanol administration in several animal models is associated with impairment of the hepatic sirtuin 1 (SIRT1)-AMP-activated kinase (AMPK) axis, a central signaling system controlling the pathways of lipid metabolism (2, 18, 38, 39).

The activation of SIRT1-AMPK signaling in several metabolic tissues including liver has been found to increase rates of fatty acid oxidation and repress lipogenesis largely by modulating activity of PPAR-γ coactivator-α (PGC-1α)/PPARα or SREBP-1 through deacetylation and phosphorylation, respectively (6, 7, 22, 32, 38). Interestingly, the SIRT1-AMPK axis has emerged as a major signaling system in regulating adiponectin signaling and in the lipid lowering action of adiponectin (27, 40).

Adiponectin is a 30-kDa protein primarily expressed and secreted from adipose tissue, and subsequently circulated in serum (27, 40). Adiponectin is present in the serum as three oligomeric complexes: namely, high (HMW)-, middle-, and low-molecular-weight forms. Accumulating evidence has suggested that adiponectin exerts its biological activities in an oligomer-dependent manner. Two major adiponectin receptors (AdipoR1 and -R2) serve as transducers of adiponectin-mediated signaling, leading to increased fatty acid oxidation and reduced fat accumulation in several organs including liver (27, 40).

Considerable evidence has suggested a pivotal role for adiponectin in the development of alcoholic fatty liver (27, 40). Dysregulation of adiponectin and hepatic AdipoR1/R2 expression can lead to accumulation of hepatic fat in several animal models of alcoholic liver steatosis (8, 9, 11, 31, 33, 35, 37). Administration of recombinant adiponectin has been shown to ameliorate liver steatosis in mouse models of alcoholic- and nonalcoholic fatty liver disease (35). In chronically ethanol-fed animals, induction of adiponectin or activation of AdipoR1/R2 through dietary or pharmacological supplements alleviated liver steatosis and injury (9, 11, 31, 37). Although the precise cellular and molecular mechanisms whereby ethanol dysregulates the expression of adiponectin remain to be established, it has been suggested that peroxisome proliferator-activated receptor-γ (PPAR-γ) may be involved (4, 27, 40).

PPAR-γ is a transcription factor known to be involved in the regulation of lipid metabolism and energy homeostasis and has been implicated in regulating adiponectin gene expression in adipose tissue (4, 40). Activation of PPAR-γ by a group of selective compounds known as thiazolidinediones (TZDs) has been shown to lead to increases in the transcription, translation, and secretion of adiponectin from adipose tissue, resulting in elevated serum levels of the protein, especially the HMW isoform. (4, 19). Pioglitazone, one of the TZDs, has been shown to prevent alcohol-induced liver injury in rats. It is possible that induction of adiponectin by activation of PPAR-γ may contribute to these hepatic protective effects (34).

Several lines of evidence have shown that another TZD, rosiglitazone, improves steatosis and normalizes liver enzyme levels in patients with nonalcoholic fatty liver disease and in some rodent models (4). The molecular mechanisms of such effects appear to involve upregulation of adiponectin in adipose tissue (4, 19). However, the benefits of rosiglitazone for liver injury are controversial. One study has shown that rosiglitazone treatment dramatically increased liver steatosis in ob/ob mice partially through activation of hepatic PPAR-γ (14).

In this study, we examined the effects of rosiglitazone treatment on the development of alcoholic fatty liver in mice and explored the involvement of adiponectin-SIRT1-AMPK signaling in the action of rosiglitazone.

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American Journal of Physiology-Gastrointestinal and Liver Physiology, v. 298, issue 3, p. G364-G374