Ces1d deficiency protects against high-sucrose diet-induced hepatic triacylglycerol accumulation

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Triacylglycerol accumulation in the liver is a hallmark of NAFLD. Metabolic studies have confirmed that increased hepatic de novo lipogenesis (DNL) in humans contributes to fat accumulation in the liver and to NAFLD progression. Mice deficient in carboxylesterase (Ces)1d expression are protected from high-fat diet-induced hepatic steatosis. To investigate whether loss of Ces1d can also mitigate steatosis induced by over-activated DNL, WT and Ces1d-deficient mice were fed a lipogenic high-sucrose diet (HSD). We found that Ces1d-deficient mice were protected from HSD-induced hepatic lipid accumulation. Mechanistically, Ces1d deficiency leads to activation of AMP-activated protein kinase and inhibitory phosphorylation of acetyl-CoA carboxylase. Together with our previous demonstration that Ces1d deficiency attenuated high-fat diet-induced steatosis, this study suggests that inhibition of CES1 (the human ortholog of Ces1d) might represent a novel pharmacological target for prevention and treatment of NAFLD. Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Triacylglycerol accumulation in the liver is a hallmark of NAFLD. Metabolic studies have confirmed that increased hepatic de novo lipogenesis (DNL) in humans contributes to fat accumulation in the liver and to NAFLD progression. Mice deficient in carboxylesterase (Ces)1d expression are protected from high-fat diet-induced hepatic steatosis. To investigate whether loss of Ces1d can also mitigate steatosis induced by over-activated DNL, WT and Ces1d-deficient mice were fed a lipogenic high-sucrose diet (HSD). We found that Ces1d-deficient mice were protected from HSD-induced hepatic lipid accumulation. Mechanistically, Ces1d deficiency leads to activation of AMP-activated protein kinase and inhibitory phosphorylation of acetyl-CoA carboxylase. Together with our previous demonstration that Ces1d deficiency attenuated high-fat diet-induced steatosis, this study suggests that inhibition of CES1 (the human ortholog of Ces1d) might represent a novel pharmacological target for prevention and treatment of NAFLD. Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder that is increasing in prevalence with the global epidemic of obesity in adults and children (1Bedogni G. Miglioli L. Masutti F. Tiribelli C. Marchesini G. Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study.Hepatology. 2005; 42: 44-52Crossref PubMed Scopus (1022) Google Scholar, 2Younossi Z.M. Koenig A.B. Abdelatif D. Fazel Y. Henry L. Wymer M. 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Inhibitors of hepatic microsomal triacylglycerol hydrolase decrease very low density lipoprotein secretion.FASEB J. 2003; 17: 1685-1687Crossref PubMed Scopus (107) Google Scholar, 15Gilham D. Alam M. Gao W. Vance D.E. Lehner R. Triacylglycerol hydrolase is localized to the endoplasmic reticulum by an unusual retrieval sequence where it participates in VLDL assembly without utilizing VLDL lipids as substrates.Mol. Biol. Cell. 2005; 16: 984-996Crossref PubMed Scopus (67) Google Scholar). Loss of Ces1d enhances insulin sensitivity and protects from high-fat diet-induced liver steatosis by increasing FA oxidation and decreasing hepatic DNL (16Lian J. Wei E. Groenendyk J. Das S.K. Hermansson M. Li L. Watts R. Thiesen A. Oudit G.Y. Michalak M. et al.Ces3/TGH Deficiency Attenuates Steatohepatitis.Sci. Rep. 2016; 6: 25747Crossref PubMed Scopus (29) Google Scholar). To specifically investigate whether ablation of Ces1d expression can alleviate steatosis induced by over-activated lipogenesis, we challenged Ces1d-deficient mice with a high-sucrose diet (HSD). Here, we show that Ces1d deficiency protects against high-carbohydrate-induced liver lipid accumulation by inhibiting the key lipogenic enzyme, acetyl-CoA carboxylase (ACC). All animal procedures were conducted in compliance with protocols approved by the University of Alberta's Animal Care and Use Committee and in accordance with the Canadian Council on Animal Care policies and regulations. Sixteen-week-old male Ces1d-deficient mice (Ces1d−/−) and WT mice of C57BL/6J background were used in the experiments (16Lian J. Wei E. Groenendyk J. Das S.K. Hermansson M. Li L. Watts R. Thiesen A. Oudit G.Y. Michalak M. et al.Ces3/TGH Deficiency Attenuates Steatohepatitis.Sci. Rep. 2016; 6: 25747Crossref PubMed Scopus (29) Google Scholar). WT and Ces1d−/− mice were maintained on a 12 h light (7:00 AM to 7:00 PM)/12 h dark (7:00 PM to 7:00 AM) cycle, controlled for temperature and humidity, and were fed either a chow diet (5% fat and 0.02% cholesterol; PicoLab Laboratory Rodent Diet 5L0D) or a HSD (74% kcal from sucrose, fat-free; MP Biomedical, #901683; supplemental Table S1) for 8 weeks. Blood and tissues were collected after 16 h fasting or after 16 h fasting followed by 6 h refeeding. Energy expenditure and fuel oxidation were assessed using the Oxymax CLAMS (Columbus Instruments). Mice were acclimated in individual chambers for 1 day before data recording. Measurements of in vivo oxygen consumption and carbon dioxide production were performed every 14 min over 2 days and used to calculate the respiratory exchange ratio (RER). Food intake was monitored during the procedure. Whole-body lean and fat masses were determined in mice by an EchoMRI™ system before and after 8 weeks of HSD feeding. Enzymatic assays kits were used to measure plasma levels of FFAs, TGs, and ketone bodies (Wako, Japan) according to the manufacturer's instructions. Plasma insulin concentration was determined using the Multiplexing LASER Bead Assay (Eve Technologies, Canada). The lipid profile was determined in liver homogenates (1 mg of protein) by GC as previously described (17Sahoo D. Trischuk T.C. Chan T. Drover V.A. Ho S. Chimini G. Agellon L.B. Agnihotri R. Francis G.A. Lehner R. ABCA1-dependent lipid efflux to apolipoprotein A-I mediates HDL particle formation and decreases VLDL secretion from murine hepatocytes.J. Lipid Res. 2004; 45: 1122-1131Abstract Full Te

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