Loss of SQSTM1/p62 Induces Obesity and Exacerbates Alcohol-induced Liver Injury in Aged Mice.

Abstract

Alcohol-related liver disease (ALD) is a worldwide health problem without successful treatment. Aging is associate with obesity, which are known a risk factor that aggravate ALD. We and others have previously demonstrated that chronic plus binge alcohol increases adipose tissue lipolysis and promotes alcohol-induced liver injury through the adipose-liver crosstalk. In the present study, we investigated the role of autophagy receptor protein SQSTM1/p62 in adipose-liver crosstalk and the effects of aging and obesity in ALD. Whole-body p62 knockout (KO) and their matched wild type young (2-3 months) and aged (13-15 months) mice were subjected to chronic plus binge (Gao-binge) alcohol model. Adipose and liver tissues were collected for biochemical and histological analysis. p62 KO mice developed mature-onset obesity in aged mice with increased both white and brown adipose tissue mass. Gao-binge alcohol feeding decreased both the white and adipose mass regardless of the age and genotypes of mice. Alcohol feeding increased levels of serum free fatty acids regardless of the genotypes of the mice although the serum levels of glycerol only significantly increased in alcohol fed aged p62 KO mice. Alcohol feeding increased levels of serum ALT and hepatic triglyceride (TG) in both young and aged WT and p62 KO mice, but no significant differences were found among the young WT and p62 KO mice as well as aged WT vs young WT mice. However, alcohol-fed aged p62 KO mice had significantly higher levels of serum ALT and hepatic TG as well as fibrosis and inflammation markers than alcohol-fed aged WT mice. Mechanistically, aged p62 KO mice had increased de novo lipogenesis and senescence with increased senescence associated secretory phenotype with similar increased oxidative stress compared with matched WT mice. We established a genetic obesity/metabolic syndrome mouse model with alcohol consumption. Loss of p62 in aged mice leads to obesity with metabolic syndrome that exacerbates alcohol-induced liver injury via increased de novo lipogenesis and senescence.