GSE139015
Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice
Alcohol's impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD).  Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility.  Here, we employed a hepatic-specific acid-ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp.  Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and lipid droplet compartments.  We additionally demonstrate that hepatic ceramide reduction prevents alcohol's inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri-lipid droplet ASAH expression in human ALD.  Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD. Overall design: Liver RNA from mice fed an alcohol diet mice was analyzed by RNAseq (N=4/group).  Hepatic ceramides were reduced by inducing  the transgene ASAH1, a ceramidase, in a liver-specific, dox-inducible fashion.   To assess the optimal control for transgene induction, we performed RNAseq to compare strategies varying either genetics (transgene- or transgene+ fed Etoh-dox) or diet (transgene+ mice fed an Etoh or Etoh-dox diet).