Genetic variation in human carboxylesterase CES1 confers resistance to hepatic steatosis

• Published in: Biochimica et biophysica acta. Molecular and cell biology of lipids Vol. 1863; no. 7; pp. 688 - 699
• Main Authors: Lian, Jihong, Bahitham, Wesam, Panigrahi, Rashmi, Nelson, Randal, Li, Lena, Watts, Russell, Thiesen, Aducio, Lemieux, M. Joanne, Lehner, Richard
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2018
• Subjects: Animals; Carboxylesterase; Carboxylic Ester Hydrolases - genetics; Carboxylic Ester Hydrolases - metabolism; Chimera - genetics; Diet, High-Fat - adverse effects; Disease Models, Animal; Female; Genetic Predisposition to Disease; Humanized mice; Humans; Lipid droplets; Lipid Metabolism - genetics; Lipids - blood; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Non-alcoholic Fatty Liver Disease - blood; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Obesity - blood; Obesity - etiology; Obesity - metabolism; Polymorphism, Single Nucleotide; Single nucleotide polymorphism; Steatosis; VLDL; NAFLD; Lipid droplets; ATGL; MTP; WAT; NASH; Carboxylesterase; Humanized mice; Steatosis; CES or Ces; ChREBP; TG; TGH; AAV; NEFA; VLDL; Es-x; TBG; FAS; LDs; SCD1; Single nucleotide polymorphism; PL
• ISSN: 1388-1981; 1879-2618
• DOI: 10.1016/j.bbalip.2018.04.002

Obesity often leads non-alcoholic fatty liver disease, insulin resistance and hyperlipidemia. Expression of carboxylesterase CES1 is positively correlated with increased lipid storage and plasma lipid concentration. Here we investigated structural and metabolic consequences of a single nucleotide polymorphism in CES1 gene that results in p.Gly143Glu amino acid substitution. We generated a humanized mouse model expressing CES1WT (control), CES1G143E and catalytically dead CES1S221A (negative control) in the liver in the absence of endogenous expression of the mouse orthologous gene. We show that the CES1G143E variant exhibits only 20% of the wild-type lipolytic activity. High-fat diet fed mice expressing CES1G143E had reduced liver and plasma triacylglycerol levels. The mechanism by which decreased CES1 activity exerts this hypolipidemic phenotype was determined to include decreased very-low density lipoprotein secretion, decreased expression of hepatic lipogenic genes and increased fatty acid oxidation as determined by increased plasma ketone bodies and hepatic mitochondrial electron transport chain protein abundance. We conclude that attenuation of human CES1 activity provides a beneficial effect on hepatic lipid metabolism. These studies also suggest that CES1 is a potential therapeutic target for non-alcoholic fatty liver disease management. •Human carboxylesterase 1 is positively correlated with lipid storage and secretion.•SNP in CES1 gene resulting in p.Gly143Glu substitution reduces CES1 activity.•Humanized mice expressing p.Gly143Glu are protected from hepatic steatosis.