ADIPOSE‐SPECIFIC LIPIN‐1 OVEREXPRESSION DISRUPTS HEPATIC ADIPONECTIN SIGNALING AND AGGRAVATES ALCOHOLIC STEATOHEPATITIS IN MICE

ADIPOSE‐SPECIFIC LIPIN‐1 OVEREXPRESSION DISRUPTS HEPATIC ADIPONECTIN SIGNALING AND AGGRAVATES ALCOHOLIC STEATOHEPATITIS IN MICE

You M

Alcoholism-Clinical and Experimental Research

2019

2019-06

Lipin‐1 is a pivotal regulator of lipid metabolism and inflammation and is involved in adipocyte development and maturation. Adiponectin is a hormone largely secreted by adipocytes. In adipocytes, lipin‐1 and adiponectin exhibit cross‐regulation. In the present study, we investigated whether and how adipose lipin‐1‐adiponectin axis contributes to the development and progression of alcoholic steatohepatitis. The effects of ethanol on adipose lipin‐1 and experimental alcoholic steatohepatitis were assessed in cultured 3T3‐L1 adipocytes and in transgenic mice overexpressing lipin‐1 in adipose (LPIN1‐Tg). In cultured 3T3‐adipocytes, ethanol exposure perturbed lipin‐1 signaling by inhibiting lipin‐1 expression, interfering lipin‐1 pre‐mRNA splicing and inducing nucleocytoplasmic shuttling of lipin‐1. Furthermore, secretion of adiponectin into 3T3‐L1 adipocytes culture medium was markedly enhanced by overexpression of lipin‐1. Consistent with the in vitro cell culture findings, feeding LPIN1‐Tg mice with an ethanol‐containing liquid diet resulted in substantial increases in serum concentrations of total and HMW adiponectin compared to ethanol‐fed WT mice. Surprisingly, despite drastically elevated circulating adiponectin levels, ethanol‐fed LPIN1‐Tg mice showed the rapid onset and progression of steatosis, inflammation, hepatobiliary damage and mild liver fibrosis. Further mechanistic studies revealed that adipose‐specific lipin‐1 overexpression exacerbated ethanol‐mediated inhibitory effects on mRNA abundance of hepatic adiponectin receptors in mice. Concurrently, adipose‐specific lipin‐1 overexpression severely suppressed protein expression of sirtuin (Sirt) 1, one of the critical components in mediating hepatic adiponectin signaling, in mice after ethanol administration. Altogether, our findings suggest that adipose‐specific lipin‐1 overexpression may in whole or in part cause disruption of hepatic adiponectin‐Sirt1 signaling routes and ultimately exacerbate alcoholic steatohepatitis in mice.

Substance Abuse

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