Adiponectin deficiency rescues high-fat diet-induced hepatic injury, apoptosis and autophagy loss despite persistent steatosis

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Abstract

BACKGROUND & AIMS:

Low levels of adiponectin (APN), an adipose-derived adipokine, are associated with obesity and nonalcoholic steatohepatitis although its role in high-fat diet-induced hepatic injury and steatosis remains unclear. Here we hypothesized that APN deficiency alters fat diet-induced hepatic function. To this end, we examined the effect of APN deficiency on high-fat diet-induced hepatic injury, apoptosis and steatosis.

METHODS:

Adult wild type and APN knockout mice were fed a low- or high-fat diet for 20 weeks. Serum levels of liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholesterol, hepatic triglycerides, steatosis, pro-inflammatory cytokines, apoptosis and autophagy were examined.

RESULTS:

High-fat feeding led to elevated body (48.2%) and liver weights (18.8%), increased levels of ALT (87.8%), serum cholesterol (104.4%), hepatic triglycerides (305.6%) and hepatic fat deposition as evidenced by Oil Red O staining, along with a reduced AST/ALT ratio and unchanged AST. Although APN knockout itself did not affect hepatic function and morphology, it reconciled fat diet-induced hepatic injury (P < 0.05 vs WT-HF group) without reversing changes in body and liver weights, serum cholesterol and hepatic steatosis. In addition, fat diet intake promoted AMPK phosphorylation, p62 accumulation and apoptosis, including elevated Bax and cleaved Caspase-3 and downregulated Bcl-2, along with suppressed phosphorylation of Akt, STAT3 and JNK, and the autophagy makers Atg7, Beclin-1 and LC3B (P < 0.05 vs WT-LF group) without affecting hepatic interlelukin-6 and tumor necrosis factor-α levels, the effects were reversed or significantly attenuated by APN knockout (P < 0.05 vs WT-HF group). In vitro study using HepG2 cells revealed that STAT3 activation rescued palmitic acid-induced cell injury whereas STAT3 inhibition nullified APN knockdown-offered beneficial effects.

CONCLUSIONS:

Our results revealed that high-fat diet intake promotes hepatic steatosis, apoptosis and interrupted autophagy. APN knockout elicits protective effect against hepatic injury possibly associated with autophagy regulation despite persistent hepatic steatosis.

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