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. 2010 Mar;298(3):G364-74.
doi: 10.1152/ajpgi.00456.2009. Epub 2009 Dec 10.

Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice

Zheng Shen  1 , Xiaomei Liang, Christopher Q Rogers, Drew Rideout, Min You
Affiliations

Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice

Zheng Shen et al. Am J Physiol Gastrointest Liver Physiol. 2010 Mar.

Abstract

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-gamma (PPAR-gamma) 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-gamma 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.

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Figures

Fig. 1.
Fig. 1.
Rosiglitazone attenuated alcoholic fatty liver in mice. Hematoxylin and eosin stain (original magnification × 20) of liver sections (A), hepatic triglyceride (TG) content (B), plasma aspartate aminotransferase (AST) levels (C), and plasma alanine aminotransferase (ALT) levels (D) of mice fed a polyunsaturated fatty acid (PUFA) control diet (C), a PUFA diet plus 3 mg·kg−1·day−1 rosiglitazone (R3), a PUFA diet plus 10 mg·kg−1·day−1 rosiglitazone (R10), or PUFA plus ethanol diets without rosiglitazone (E) or plus rosiglitazone (E+R3, E+R10). All data are expressed as means ± SD; n = 6–8 animals. Means without a common letter differ, P < 0.05.
Fig. 2.
Fig. 2.
Rosiglitazone increased circulating adiponectin and normalized plasma high-molecular-weight (HMW) form of adiponectin in ethanol-fed mice. Circulating adiponectin concentrations (A), plasma HMW levels of adiponectin (B), and relative adipose mRNA levels of adiponectin, TNF-α, peroxisomal proliferator-activated receptor-γ (PPAR-γ), sirtuin 1 (SIRT1), and uncoupling protein-2 (UCP2) (C) of mice fed diets as described in Fig. 1. All data are expressed as means ± SD; n = 6–8 animals. Means without a common letter differ, P < 0.05.
Fig. 3.
Fig. 3.
Rosiglitazone increased the mRNA expression levels of adiponectin receptors in the livers of ethanol-fed mice. Relative hepatic mRNA levels of adiponectin receptors AdipoR1 and AdipoR2 (A), relative hepatic mRNA (B), and nuclear protein (C) levels of PPAR-γ of mice fed diets as described in Fig. 1. All data are expressed as means ± SD; n = 6–8 animals. Means without a common letter differ, P < 0.05.
Fig. 4.
Fig. 4.
Rosiglitazone administration activated hepatic SIRT1 activity in ethanol-fed mice. Hepatic SIRT1 mRNA (A), SIRT1 protein levels (B), acetylation of PPAR-γ coactivator-α (PGC-1α) or forkhead transcription factor O 1 (FoxO1) (C), and relative PGC-1α or FoxO1 acetylation (D) of mice fed various diets as described in Fig. 1. PGC-1α was immunoprecipitated from liver extracts then immunoblotted with an anti-acetylated lysine (Ac-Lys) antibody to determine the extent of PGC-1α acetylation. The acetylation levels of FoxO1 were determined by use of an anti-acetylated FoxO1 (Ac-FoxO1) antibody. All data are expressed as means ± SD; n = 6–8 animals. Means without a common letter differ, P < 0.05. IP, Immunoprecipitated; IB, immunoblotted.
Fig. 5.
Fig. 5.
Rosiglitazone stimulated hepatic AMP-activated kinase (AMPK) activity in ethanol-fed mice. A: Western blots were performed by using anti-phosphorylated-AMPKα (anti-p-AMPKα), anti-AMPKα, and anti-phosphorylated acetyl CoA carboxylase (p-ACC) antibodies from liver extracts of mice fed various diets as described in Fig. 1. β-Actin protein band was used to confirm equal loading and to normalize the data. B: relative levels of p-AMPKα, AMPKα, and p-ACC. Western blots were quantified by a PhosphorImager and MultiAnalyst (Bio-Rad) software analysis. All data are expressed as means ± SD; n = 6–8 animals. Means without a common letter differ, P < 0.05.
Fig. 6.
Fig. 6.
Rosiglitazone induced expression of genes encoding fatty acid oxidation enzymes and blocked the expression of genes encoding lipogenic enzymes in ethanol-fed mice. Relative mRNA levels of PGC-1α, retinoid X receptor α (RXRα), and PPARα signaling-regulated fatty acid oxidation enzymes (A), acetyl-histone H3-Lys9 (Ac-histone H3-Lys 9) and histone H3 levels (B), and relative mRNA levels of lipogenic enzymes (C) in the livers of mice fed various diets as described in Fig. 1. ACCα, acetyl-coenzyme A carboxylase α; MCAD, medium-chain acyl-CoA dehydrogenase; CPTI, carnitine palmitoyltransferase I. All data are expressed as means ± SD; n = 5–8 animals. Means without a common letter differ, P < 0.05.
Fig. 7.
Fig. 7.
Rosiglitazone normalized lipin 1 expression levels in the livers and adipose tissues of ethanol-fed mice. A: hepatic or adipose lipin 1 mRNA. B: liver cytosolic lipin 1 protein levels of mice fed various diets as described in Fig. 1. All data are expressed as means ± SD; n = 5–8 animals. Means without a common letter differ, P < 0.05.
Fig. 8.
Fig. 8.
Adiponectin upregulated SIRT1 and stimulated AMPK activity in rat H4IIEC3 cells. A: H4IIEC3 cells were starved in serum-free DMEM overnight, and full-length mouse recombinant adiponectin (flAcrp) was added at the indicated concentrations for 18 h. B: H4IIEC3 cells transfected with AdipoR1 small silencing RNA (shRNA) or AdipoR2 shRNA plasmid were treated with flAcrp (1 μg/ml) for 18 h. C: H4IIEC3 cells transfected with AMPKα shRNA plasmid were treated with flAcrp (1 μg/ml) for 18 h. D: H4IIEC3 cells transfected with SIRT1 shRNA were treated with flAcrp (1 μg/ml) for 18 h. E: H4IIEC3 cells were starved in serum-free DMEM overnight and pretreated with flAcrp (1 μg/ml) followed by addition of ethanol (63 mM) for 18 h. SIRT1 protein levels or phosphorylated-AMPKα (p-AMPKα) were detected by Western blots with anti-SIRT1 and anti-p-AMPKα antibodies, respectively. The data represent at least 3 replications.
Fig. 9.
Fig. 9.
Proposed role of adiponectin-SIRT1-AMPK signaling in the protective effects of rosiglitazone against alcoholic liver steatosis in mice. Ac-histone H3-Lys9, histone H3 at acetylated lysine 9; FA, free fatty acids; PAP1, phosphatidate phosphatase type-1.
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