Activation of peroxisome proliferator-activated receptor-γ by rosiglitazone improves lipid homeostasis at the adipose tissue-liver axis in ethanol-fed mice

Abstract

The development of alcohol-induced fatty liver is associated with a reduction of white adipose tissue (WAT). Peroxisome proliferator-activated receptor (PPAR)-γ prominently distributes in the WAT and plays a crucial role in maintaining adiposity. The present study investigated the effects of PPAR-γ activation by rosiglitazone on lipid homeostasis at the adipose tissue-liver axis. Adult C57BL/6 male mice were pair fed liquid diet containing ethanol or isocaloric maltose dextrin for 8 wk with or without rosiglitazone supplementation to ethanol-fed mice for the last 3 wk. Ethanol exposure downregulated adipose PPAR-γ gene and reduced the WAT mass in association with induction of inflammation, which was attenuated by rosiglitazone. Ethanol exposure stimulated lipolysis but reduced fatty acid uptake capacity in association with dysregulation of lipid metabolism genes. Rosiglitazone normalized adipose gene expression and corrected ethanol-induced lipid dyshomeostasis. Ethanol exposure induced steatosis and upregulated inflammatory genes in the liver, which were attenuated by rosiglitazone. Hepatic peroxisomal fatty acid β-oxidation was suppressed by ethanol in associated with inhibition of acyl-coenzyme A oxidase 1. Rosiglitazone elevated plasma adiponectin level and normalized peroxisomal fatty acid β-oxidation rate. However, rosiglitazone did not affect ethanol-reduced very low-density lipoprotein secretion from the liver. These results demonstrated that activation of PPAR-γ by rosiglitazone reverses ethanol-induced adipose dysfunction and lipid dyshomeostasis at the WAT-liver axis, thereby abrogating alcoholic fatty liver.

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

“…In alcohol-treated mice, the PPARγ agonists, rosiglitazone and pioglitazone, increase circulating levels of adiponectin and expression of its receptors in the liver that is associated with SIRT1-AMPK signaling activation. This pathway correlates with the enhanced expression of fatty acid oxidation enzymes and reduction of alcohol-induced steatosis [207][208][209][210][211][212][213] . In addition, PPARγ agonists have anti-inflammatory effects that reduce cytokine expression such as TNF-α, IL-6 and MCP-1 in alcohol-fed mice [207] .…”

“…This pathway correlates with the enhanced expression of fatty acid oxidation enzymes and reduction of alcohol-induced steatosis [207][208][209][210][211][212][213] . In addition, PPARγ agonists have anti-inflammatory effects that reduce cytokine expression such as TNF-α, IL-6 and MCP-1 in alcohol-fed mice [207] . The altered intestinal microflora during chronic alcohol consumption has recently been focused as a therapeutic target in ALD.…”

MFG-E8 and HMGB1 Are Involved in the Mechanism Underlying Alcohol-Induced Impairment of Macrophage Efferocytosis

“…We treated mice with alcohol using our standard protocol described previously (36). Briefly, C57BL/6 mice from Harlan at 10 wks old were pair fed with a modified Lieber-DeCarli alcohol liquid diet containing either ethanol or isocaloric maltose dextrin as control for 8 wks.…”

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“…8 A recent study demonstrated that moderate obesity and alcohol synergistically induced steatohepatitis, 20 further supporting the critical role of adipose tissue (dys) function in the development of ALD. Importantly, both rosiglitazone (a PPAR-gamma agonist mainly targeting adipocytes) 21 and recombinant adiponectin (an adipokine exclusively secreted by adipocytes) 22 improved ALD, suggesting that improving adipose tissue function represents a potential therapeutic approach for ALD.…”