Acrolein Adduct Accumulation Causes Alcoholic Liver Disease

Overview

ALD is a major cause of morbidity and mortality worldwide and in the United States, with no FDA approved therapy. Also, it remains unclear why only some heavy alcohol drinkers develop clinically relevant ALD. Poor understanding of ALD pathogenesis impedes prevention, early diagnosis, and treatment of the disease. ER stress-UPR has recently been established as a significant mechanism contributing to ALD, however the mediators and mechanisms of alcohol-induced ER stress and liver injury are not fully understood. Alcohol consumption and metabolism increases oxidative stress and LPO of PUFAs, and generates aldehydes, among which acrolein is the most reactive and toxic. Acrolein can exert potent cellular toxicity by forming irreversible covalent adducts with proteins thereby interfering with their function. Acrolein is primarily metabolized and removed by the enzyme GSTP by conjugation to GSH.

Hypothesis

Acrolein & Alcoholic Liver Disease Hypothesisleads toAlcoholGSTPdown regulationAcrolein proliferation, which promotes liver ER stress, apoptosis, steatosis & injuryAcrolein andAcrolein AdductsER stressApoptosisSteatosisInjuryAlcoholic Liver DiseaseAcrolein clearance by scavengers like hydralazine inhibits alcoholic liver diseaseHydralazine(AcroleinScavenger)

Acrolein formation and acrolein-adduct accumulation, occurring as a consequence of alcohol consumption and GSTP downregulation, is a significant event that critically mediates alcohol-induced ER stress/UPR, apoptosis and liver injury, thereby contributing to ALD pathogenesis. Acrolein clearance by scavengers will attenuate hepatic injury in ALD.

About Researcher

Principal Investigator

Swati Joshi-Barve

Swati Joshi-Barve, PhD

Assistant Professor of Medicine

E-mail Dr. Joshi-Barve

Education

PhD
Biochemistry, University of Kentucky
MS
University of Poona
BS
University of Poona

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