Ethanol withdrawal mitigates fatty liver by normalizing lipid catabolism

Paul G. Thomes, Karuna Rasineni, Li Yang, Terrence M. Donohue, Jacy L. Kubik, Mark A. McNiven, Carol A. Casey

Research output: Contribution to journalArticle

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Abstract

We are investigating the changes in hepatic lipid catabolism that contribute to alcohol-induced fatty liver. Following chronic ethanol (EtOH) 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lead to this resolution by quantifying specific catabolic parameters that returned to control levels after EtOH was withdrawn.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, EtOH withdrawal reactivates lipid catabolic processes that restore lipostasis. Male Wistar rats were fed control and EtOH liquid diets for 6 wk. Randomly chosen EtOH-fed rats were then fed control diet for 7 days. Liver triglycerides (TG), lipid peroxides, key markers of fatty acid (FA) metabolism, lipophagy, and autophagy were quantified. 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 FA transporters (FATP 2, 4, and 5) but lower quantities of peroxisome proliferator-activated receptor-α (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, whereas PPAR-α levels rose to normal. Hepatic TG and malondial-dehyde levels in EtOH-withdrawn rats declined to near control levels. EtOH withdrawal restored nuclear TFEB content, hepatic lipophagy, and autophagy activity to control levels. EtOH withdrawal reversed aberrant FA metabolism and restored lysosomal function to promote resolution of alcohol-induced fatty liver. NEW & NOTEWORTHY Here, using an animal model, we show mechanisms of reversal of fatty liver and injury following EtOH withdrawal. Our data indicate that reactivation of autophagy and lysosome function through the restoration of transcription factor EB contribute to reversal of fatty liver and injury following EtOH withdrawal.

Original languageEnglish (US)
Pages (from-to)G509-G518
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume316
Issue number4
DOIs
StatePublished - Apr 2019

Fingerprint

Fatty Liver
Autophagy
Ethanol
Lipids
Liver
Fatty Acids
Peroxisome Proliferator-Activated Receptors
Triglycerides
Transcription Factors
Lipid Peroxides
Diet
Nonesterified Fatty Acids
Alcohols
Alcohol Abstinence
Wounds and Injuries
Lysosomes
Serum
Wistar Rats
Animal Models

Keywords

  • Ethanol
  • Fatty acid
  • Oxidant stress
  • Steatosis
  • TFEB

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

Ethanol withdrawal mitigates fatty liver by normalizing lipid catabolism. / Thomes, Paul G.; Rasineni, Karuna; Yang, Li; Donohue, Terrence M.; Kubik, Jacy L.; McNiven, Mark A.; Casey, Carol A.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 316, No. 4, 04.2019, p. G509-G518.

Research output: Contribution to journalArticle

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