Ethanol Withdrawal Mitigates Fatty Liver by Normalizing Lipid Catabolism.

BACKGROUND: We are investigating the changes in hepatic lipid catabolism that contribute to alcohol-induced fatty liver. Following chronic ethanol exposure, abstinence from alcohol resolves steatosis. Here, we investigated the hepatocellular events that lead to this resolution by quantifying specific catabolic parameters that returned to control levels after EtOH was withdrawn. We hypothesized that after its chronic consumption ethanol withdrawal reactivates lipid catabolic processes that restore lipostasis.

METHODS: Male Wistar rats were fed control and EtOH liquid diets for 6 wk. Randomly chosen EtOH-fed rats were then fed control diet for seven days. Liver triglycerides (TG), lipid peroxides, key markers of fatty acid (FA) metabolism, lipophagy and autophagy were quantified.

RESULTS: Compared with controls, EtOH-fed rats had higher hepatic triglycerides, lipid peroxides and serum free fatty acids (FFA). The latter findings were associated with higher levels of fatty acid (FA) transporters (FATP 2, 4, & 5) but lower quantities of PPAR-α, which governs FA oxidation. EtOH-fed animals also had lower nuclear levels of the autophagy-regulating transcription factor EB (TFEB), associated with lower hepatic lipophagy and autophagy. After EtOH-fed rats were refed control diet for 7 days, their serum FFA levels and those of FATPs fell to control (normal) levels, while PPAR-α levels rose to normal. Hepatic TG and malondialdehyde levels in EtOH-withdrawn rats declined to near control levels. EtOH withdrawal restored nuclear TFEB content, hepatic lipophagy and autophagy activity to control levels.

CONCLUSIONS: EtOH withdrawal reversed aberrant FA metabolism and restored lysosomal function to promote resolution of alcohol-induced fatty liver.