Diverse Consequences in Liver Injury in Mice with Different Autophagy Functional Status Treated with Alcohol.Am J Pathol 2019; 189(9):1744-1762AJ
Alcoholic fatty liver disease is often complicated by other pathologic insults, such as viral infection or high-fat diet. Autophagy plays a homeostatic role in the liver but can be compromised by alcohol, high-fat diet, or viral infection, which in turn affects the disease process caused by these etiologies. To understand the full impact of autophagy modulation on alcohol-induced liver injury, several genetic models of autophagy deficiency, which have different levels of functional alterations, were examined after acute binge or chronic-plus-binge treatment. Mice given alcohol with either mode and induced with deficiency in liver-specific Atg7 shortly after the induction of Atg7 deletion had elevated liver injury, indicating the protective role of autophagy. Constitutive hepatic Atg7-deficient mice, in which Atg7 was deleted in embryos, were more susceptible with chronic-plus-binge but not with acute alcohol treatment. Constitutive hepatic Atg5-deficient mice, in which Atg5 was deleted in embryos, were more susceptible with acute alcohol treatment, but liver injury was unexpectedly improved with the chronic-plus-binge regimen. A prolonged autophagy deficiency may complicate the hepatic response to alcohol treatment, likely in part due to endogenous liver injury. The complexity of the relationship between autophagy deficiency and alcohol-induced liver injury can thus be affected by the timing of autophagy dysfunction, the exact autophagy gene being affected, and the alcohol treatment regimen.