Abstract
The liver is a major organ that controls hepatic and systemic homeostasis. Dysregulation of liver metabolism may cause liver injury. Previous studies have demonstrated that carboxylesterase 1 (CES1) regulates hepatic triglyceride metabolism and protects against liver steatosis. In the present study, we investigated whether CES1 played a role in the development of alcoholic liver disease (ALD) and methionine and choline-deficient (MCD) diet-induced liver injury. Both hepatocyte nuclear factor 4α (HNF4α) and CES1 were markedly reduced in patients with alcoholic steatohepatitis. Alcohol repressed both HNF4α and CES1 expression in primary hepatocytes. HNF4α regulated CES1 expression by directly binding to the proximal promoter of CES1. Global inactivation of CES1 aggravated alcohol- or MCD diet-induced liver inflammation and liver injury, likely as a result of increased production of acetaldehyde and reactive oxygen species and mitochondrial dysfunctions. Knockdown of hepatic CES1 exacerbated ethanol-induced steatohepatitis. These data indicate that CES1 plays a crucial role in protection against alcohol- or MCD diet-induced liver injury.
Highlights
Significant advances have been made toward understanding the pathogenesis of alcoholic liver disease (ALD)
To investigate whether carboxylesterase 1 (CES1) is associated with the development of ALD, we investigated the expression of CES1 in patients with alcoholic steatohepatitis
Hepatic CES1 mRNA level was reduced by 75% (Fig. 1A) and protein level decreased by ~85% (Fig. 1B,C)
Summary
Significant advances have been made toward understanding the pathogenesis of ALD. Alcohol-induced increases in reactive oxygen species (ROS), lipid peroxidation (LPO), acetaldehyde, fatty acid ethyl ester (FAEE), lipopolysaccharide (LPS) and protein carbonyl, etc. are directly responsible for the development of ALD3–7. Alcohol-induced increases in reactive oxygen species (ROS), lipid peroxidation (LPO), acetaldehyde, fatty acid ethyl ester (FAEE), lipopolysaccharide (LPS) and protein carbonyl, etc. Over-expression of hepatic CES1 reduces TG accumulation through promoting lipolysis and FAO. Knockdown of hepatic CES1 increases lipid accumulation by inducing lipogenesis[11,14,15]. The role of CES1 in the development of ALD or liver injury is completely unknown. Hepatocyte nuclear factor 4α (HNF4α ) is a nuclear hormone receptor that is constitutively active and regulates lipid, glucose, bile acid and drug metabolism. Loss of hepatic HNF4α causes fatty liver by inhibiting very low-density lipoprotein (VLDL) secretion[16,17]. HNF4α expression is markedly reduced in diabetes, obesity, non-alcoholic fatty liver disease (NAFLD) and high fat diet (HFD) feeding, likely resulting from increased free www.nature.com/scientificreports/. HNF4α controls the basal expression of many genes in the liver, but it is unclear whether HNF4α regulates CES1 expression
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