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Carboxylesterase 1 Protects Against Liver Injury and Is Regulated by Hepatocyte Nuclear Factor 4α
Author(s) -
Xu Jiesi,
Xu Yang,
Zhang Yanqiao
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb69
Subject(s) - alcoholic liver disease , steatohepatitis , alcohol dehydrogenase , pathogenesis , liver disease , medicine , hepatocyte , liver injury , endocrinology , cirrhosis , chemistry , fatty liver , alcohol , disease , biochemistry , in vitro
Alcoholic liver disease (ALD) is a leading cause of alcohol‐related mortality worldwide. Liver cirrhosis is the 12th leading cause of death in the US, with a total of 36,427 deaths in 2013, 49.8% of which are related to alcohol. So far, the mechanism underlying the pathogenesis of ALD is not fully understood. In addition, pharmacological interventions for ALD remain limited and less effective. In the present study, we show that both hepatocyte nuclear factor a (HNF4α) and carboxylesterase 1 (CES1) are markedly reduced in patients with alcoholic steatohepatitis. Alcohol represses both HNF4α and CES1 expression in primary hepatocytes. We further show that HNF4α controls CES1 expression by directly binding to the proximal promoter of CES1. Global inactivation of CES1 causes alcohol‐ or methionine and choline deficient (MCD) diet‐induced liver inflammation, likely as a result of elevated levels of hepatic acetaldehyde, reactive oxygen species and mitochondrial dysfunctions. Knockdown of hepatic CES1 causes ethanol‐induced steatohepatitis. Our data indicate that the HNF4α‐CES1 pathway plays a crucial role in protection against the pathogenesis of ALD. Targeting hepatic CES1 may be a plausible strategy for treatment of ALD.