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. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology. 2016; 64: 73-84Crossref PubMed Scopus (5296) Google Scholar). Hepatic steatosis results from an imbalance between import, synthesis, utilization, and/or export of lipids. Considerable evidence supports the ability of high-carbohydrate diets to upregulate hepatic de novo lipogenesis (DNL), leading to increased triacylglycerol (TG) production (3Kok N. Roberfroid M. Delzenne N. Dietary oligofructose modifies the impact of fructose on hepatic triacylglycerol metabolism.Metabolism. 1996; 45: 1547-1550Abstract Full Text PDF PubMed Scopus (108) Google Scholar). Over-consumption of simple carbohydrates in processed foods and beverages, especially fructose and sucrose, has been implicated in NAFLD development (4Nikpartow N. Danyliw A.D. Whiting S.J. Lim H. Vatanparast H. Fruit drink consumption is associated with overweight and obesity in Canadian women.Can. J. Public Health. 2012; 103: 178-182Crossref PubMed Google Scholar, 5Malik V.S. Popkin B.M. Bray G.A. Despres J.P. Hu F.B. Sugar-sweetened beverages, obesity, type 2 diabetes mellitus, and cardiovascular disease risk.Circulation. 2010; 121: 1356-1364Crossref PubMed Scopus (1138) Google Scholar). Metabolites generated during carbohydrate metabolism in the liver serve as substrates for DNL and activate the master transcription factor, carbohydrate-responsive element-binding protein (ChREBP), to induce mRNA expression of lipogenic genes, including genes encoding FAS and stearoyl-CoA desaturase 1 (SCD1) (6Abdul-Wahed A. Guilmeau S. Postic C. Sweet sixteenth for ChREBP: established roles and future goals.Cell Metab. 2017; 26: 324-341Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). Our laboratory has investigated the role of carboxylesterases in lipid metabolism, including murine carboxylesterase (Ces)1d [previously annotated as Ces3 and TG hydrolase (TGH)] (7Lehner R. Verger R. Purification and characterization of a porcine liver microsomal triacylglycerol hydrolase.Biochemistry. 1997; 36: 1861-1868Crossref PubMed Scopus (99) Google Scholar, 8Lehner R. Vance D.E. Cloning and expression of a cDNA encoding a hepatic microsomal lipase that mobilizes stored triacylglycerol.Biochem. J. 1999; 343: 1-10Crossref PubMed Scopus (116) Google Scholar, 9Dolinsky V.W. Sipione S. Lehner R. Vance D.E. The cloning and expression of a murine triacylglycerol hydrolase cDNA and the structure of its corresponding gene.Biochim. Biophys. Acta. 2001; 1532: 162-172Crossref PubMed Scopus (78) Google Scholar). Ces1d was shown to participate in basal lipolysis in adipocytes (10Wei E. Gao W. Lehner R. Attenuation of adipocyte triacylglycerol hydrolase activity decreases basal fatty acid efflux.J. Biol. Chem. 2007; 282: 8027-8035Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 11Dominguez E. Galmozzi A. Chang J.W. Hsu K.L. Pawlak J. Li W. Godio C. Thomas J. Partida D. Niessen S. et al.Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes.Nat. Chem. Biol. 2014; 10: 113-121Crossref PubMed Scopus (97) Google Scholar). In the liver, experimental evidence suggests that murine Ces1d and its human ortholog, CES1, participate in the mobilization of preformed TG for VLDL assembly (12Lehner R. Cui Z. Vance D.E. Subcellular localization, developmental expression and characterization of a liver triacylglycerol hydrolase.Biochem. J. 1999; 338: 761-768Crossref PubMed Scopus (0) Google Scholar, 13Dolinsky V.W. Douglas D.N. Lehner R. Vance D.E. Regulation of the enzymes of hepatic microsomal triacylglycerol lipolysis and re-esterification by the glucocorticoid dexamethasone.Biochem. J. 2004; 378: 967-974Crossref PubMed Scopus (106) Google Scholar, 14Gilham D. Ho S. Rasouli M. Martres P. Vance D.E. Lehner R. 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 h and oxidation were the Mice were in for 1 of in consumption and production were 2 and used to the was during the and fat were in mice by an and after 8 of HSD were used to of and to the insulin was the The lipid was in liver of by as D. Ho S. G. R. G.A. Lehner R. lipid to and decreases VLDL from murine 2004; 45: Full Text Full Text PDF PubMed Scopus Google Scholar). Hepatic FA and were by of in liver lipid to FA in the of as an (10Wei E. Gao W. Lehner R. Attenuation of adipocyte triacylglycerol hydrolase activity decreases basal fatty acid efflux.J. Biol. Chem. 2007; 282: 8027-8035Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). was by a to Blood were by an with W. J. Z. E. The is for and J. 2012; PubMed Scopus Google Scholar). Mice were and with Blood was collected and and h after TG was by a were in sucrose, 1 by and to used in this study lipase FAS hydrolase from protein kinase and and and and and lipase and and was by and by The of the on the were by the liver was cDNA was from 2 of by and was with the were with the were used to mRNA to that of a are in supplemental Table All were by In lipogenesis with as was as with M. J. of on lipogenesis in J. PubMed Scopus Google Scholar). In mice fed a HSD for 8 were for of was and were 1 h after liver lipid lipids were from on with acid and by to in the lipid was by the was in the lipid by Mice were for 16 h to of of were the All are as between was by from studies in WT and Ces1d−/− mice fed on chow diet and HSD were by followed by were and Sixteen-week-old Ces1d−/− and WT mice were fed with HSD or chow diet for 8 weeks. WT mice show in between the chow and HSD Ces1d−/− mice a the of the during the 8 of the was in Ces1d−/− mice on chow diet and 8 of in was between Ces1d-deficient and WT mice on either diet The the of suggests that Ces1d−/− mice fed a chow diet WT mice during the as adults Ces1d−/− mice fed HSD to with the Ces1d−/− mice fed a chow diet Ces1d−/− mice and/or on chow diet and HSD in of fat and in WT and Ces1d−/− mice HSD HSD increased fat and in the WT this was in Ces1d−/− mice that the in the Ces1d−/− mice from with WT The 16 h fasting in Ces1d−/− mice either or with WT Ces1d−/− mice in the HSD in the to basal lipolysis in Ces1d−/− adipocytes (10Wei E. Gao W. Lehner R. Attenuation of adipocyte triacylglycerol hydrolase activity decreases basal fatty acid efflux.J. Biol. Chem. 2007; 282: 8027-8035Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 11Dominguez E. Galmozzi A. Chang J.W. Hsu K.L. Pawlak J. Li W. Godio C. Thomas J. Partida D. Niessen S. et al.Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes.Nat. Chem. Biol. 2014; 10: 113-121Crossref PubMed Scopus (97) Google Scholar). that the fat in Ces1d−/− mice fed HSD is to increased lipolysis in with this was in the Ces1d−/− mice on diets FA Blood and were also in this and was between in either diet that the in the was by the diets or by the Ces1d−/− mice chow diet WT mice during the dark were in HSD between WT and Ces1d−/− mice the were in Ces1d−/− and WT mice after HSD an increased of carbohydrates as the Ces1d−/− mice increased fed either the chow diet or the HSD with the WT on carbohydrate fat as an was in between Ces1d−/− and WT mice after HSD To whether Ces1d deficiency against steatosis induced by DNL, were on collected after DNL is HSD increased liver in WT mice in Ces1d−/− mice HSD induced an in hepatic TG in WT HSD on hepatic TG in Ces1d−/− with TG from Ces1d−/− mice HSD also increased liver and in WT and Ces1d−/− mice in Ces1d−/− mice was with WT mice that the HSD in this study was a to FA hepatic FA in lipid was 8 of HSD WT and Ces1d−/− mice a decrease in hepatic of acid and and and acid acid that can in the liver was increased by HSD in the in Ces1d−/− mice was in WT mice is with the liver lipid and the of attenuated TG HSD increased hepatic mRNA expression of the genes, and were found between WT and Ces1d−/− mice was in TG between WT and Ces1d−/− mice fed HSD The was in the of that the in the liver lipid was by VLDL is by carbohydrate leading to transcription of genes encoding lipogenic enzymes and increased DNL in the liver (6Abdul-Wahed A. Guilmeau S. Postic C. Sweet sixteenth for ChREBP: established roles and future goals.Cell Metab. 2017; 26: 324-341Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). and have been has been for activation by activation of expression of the J. M. S. novel in 2012; PubMed Scopus Google Scholar). In the HSD increased hepatic expression of encoding the in WT and Ces1d−/− mice a hepatic expression of target genes, liver and were induced in mice with between WT and Ces1d−/− mice results that ablation of Ces1d expression the of lipogenic expression by hepatic transcription of lipogenic genes by transcription of DNL G. J. Y. Regulation of element-binding by and PubMed Scopus Google Scholar). and its were to induce activity N. L. Godio C. E. A. E. The is a 2007; PubMed Scopus Google Scholar, L. S. M. liver is in to Biol. Chem. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). 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Chem. 2004; Full Text Full Text PDF PubMed Scopus Google high-carbohydrate diet expression of in the liver of WT and Ces1d−/− mice with WT Ces1d−/− mice with attenuated expression in the the target lipogenic FAS and protein between WT and Ces1d−/− of key of lipogenesis, was induced by HSD to a in WT and Ces1d−/− mice the phosphorylation of was in Ces1d−/− mice with the WT in diet liver activity in Ces1d−/− mice to the attenuated liver TG accumulation after HSD is that inhibiting activity and DNL N. G. of fatty acid and by of AMP-activated protein J. PubMed Scopus Google Scholar, D. Purification and characterization of the AMP-activated protein of acetyl-CoA carboxylase kinase and kinase J. PubMed Scopus Google Scholar). In with this increased of in the of Ces1d−/− mice suggests activity HSD also increased the of and in the was found between WT and Ces1d−/− mice and also in between WT and Ces1d−/− mice that the of Ces1d deficiency on the of and is liver DNL was by of lipids in WT and Ces1d−/− mice in the was in the of the and in the liver that lipids from in the liver are between WT and Ces1d−/− The of lipids in also between WT and Ces1d−/− mice Hepatic expression of FA genes, and between or diet after fasting To investigate whether the attenuated TG accumulation in the liver of Ces1d−/− mice to in lipid lipase hepatic expression of and its was The mRNA expression of encoding an of J. of 2 enhances hepatic and high-fat diet-induced liver 2014; PubMed Scopus (78) Google was in the of Ces1d−/− mice fed chow diet with the WT on the was between the has been that and lipolysis in the liver C. Y. Gao Li L. Y. F. L. J. 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C. et of simple and by the Metab. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). HSD expression of in of WT and Ces1d−/− mice with that the in and lipid metabolism in Ces1d−/− mice were to by Hepatic mRNA expression of key enzymes in was expression of was found in Ces1d−/− mice fed HSD with the WT were in the expression of between fed either diet in was between WT and Ces1d−/− mice of diet in the was found in insulin after between that the metabolism in mice fed HSD was by Ces1d increased hepatic was in Ces1d−/− mice fed chow diet with WT was between the that the of HSD-induced liver TG accumulation in Ces1d−/− mice was to a of from lipid to The prevalence of NAFLD in humans has increased with the in carbohydrate consumption M. G. E. and nonalcoholic fatty liver disease: fructose as a of PubMed Google Scholar). 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Hepatic is for the of and on and lipogenic Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google and for In the mice Ces1d were protected from HSD liver TG accumulation. activation of the and to a by HSD in Ces1d-deficient and WT that the attenuated hepatic TG accumulation in the Ces1d-deficient mice was to an of a of lipogenic enzymes are by has as a key of and an role in lipid and carbohydrate has been that lipid phosphorylation of key enzymes in FA and N. G. of fatty acid and by of AMP-activated protein J. PubMed Scopus Google Scholar, D. Purification and characterization of the AMP-activated protein of acetyl-CoA carboxylase kinase and kinase J. PubMed Scopus Google Scholar, D. common protein kinase the enzymes of fatty acid and PubMed Scopus Google Scholar, R. of of phosphorylation by AMP-activated kinase and inhibition of induced by PubMed Scopus Google Scholar). of FA by J.W. L. kinase the of AMP-activated protein kinase and a Biol. PubMed Scopus Google Scholar). activation of has been shown to decrease hepatic DNL and from diet-induced steatosis A. M. D. activation of steatosis on a 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). activation and phosphorylation were in Ces1d-deficient mice fed The by is in the of Ces1d−/− mice and it is to the in metabolism as fat and increased to hepatic lipid in Ces1d−/− mice with WT the of the was has been that phosphorylation of of to to lipolysis S. phosphorylation of lipid protein its by 2016; PubMed Scopus Google Scholar). with the in activation in the of Ces1d−/− Ces1d and its human ortholog, CES1, have been shown to a role in the of lipid metabolism J. R. Lehner R. in lipid from to Cell. PubMed Scopus Google Scholar). Ces1d participates in basal lipolysis in adipocytes (10Wei E. Gao W. Lehner R. Attenuation of adipocyte triacylglycerol hydrolase activity decreases basal fatty acid efflux.J. Biol. Chem. 2007; 282: 8027-8035Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 11Dominguez E. Galmozzi A. Chang J.W. Hsu K.L. Pawlak J. Li W. Godio C. Thomas J. Partida D. Niessen S. et al.Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes.Nat. Chem. Biol. 2014; 10: 113-121Crossref PubMed Scopus (97) Google and in the of substrates for the assembly of hepatic VLDL R. Vance D.E. Cloning and expression of a cDNA encoding a hepatic microsomal lipase that mobilizes stored triacylglycerol.Biochem. J. 1999; 343: 1-10Crossref PubMed Scopus (116) Google Scholar). The of Ces1d decreases VLDL in liver steatosis E. Y. J. H. R. V.W. G. Lehner R. Loss of in mice decreases and Metab. 2010; Full Text Full Text PDF PubMed Scopus Google to FA from to the liver in Ces1d mice E. Y. J. H. R. V.W. G. Lehner R. Loss of in mice decreases and Metab. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). increased FA oxidation was in the Ces1d-deficient and Ces1d mice E. Y. J. H. R. V.W. G. Lehner R. Loss of in mice decreases and Metab. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Wei E. A.D. Li L. A.D. J. Sipione S. G.A. Lehner R. of carboxylesterase hydrolase decreases lipids without steatosis in 2012; PubMed Scopus Google also to the prevention of liver lipid accumulation. We in our previous study that ablation of Ces1d expression protects mice from high-fat diet-induced liver steatosis by decreasing hepatic DNL, increasing FA and insulin sensitivity (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). our in the Ces1d of lipogenesis in Ces1d−/− mice after high-fat diet was to expression of target including and of of the The between the studies by the diets In the mRNA was in the Ces1d−/− this the expression of target is to the of of lipogenic enzymes in the HSD liver FA oxidation was in the high-fat Ces1d-deficient mice with the WT mice fed the diet (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). In the high-sucrose Ces1d−/− we of and expression of genes in FA oxidation in the liver in to FA to the liver and a carbohydrate as the by the increased of carbohydrates as the in HSD also decrease the of substrates from carbohydrates for DNL in the liver of Ces1d−/− to attenuated lipid the the FA in the also to lipid in the of Ces1d−/− TG was in Ces1d−/− mice with WT mice an of is with previous in Ces1d−/− mice fed chow TG with E. Y. J. H. R. V.W. G. Lehner R. Loss of in mice decreases and Metab. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar, J. W. R. R. Li L. Watts R. Thiesen A. Lehner R. in human carboxylesterase CES1 to hepatic Biophys. Biol. PubMed Scopus Google Scholar). In the HSD TG VLDL and was between Ces1d−/− and WT that the in liver lipid animal was to in VLDL In lipogenesis experiments as the lipogenic show in WT and Ces1d−/− mice during the lipogenesis is most this that lipid from was by Ces1d HSD acetyl-CoA from carbohydrate metabolism to lipogenesis A. A. F. L. of high-carbohydrate and high-fat diets on hepatic lipogenesis in J. 2014; PubMed Scopus Google Scholar). The increased carbohydrate in Ces1d−/− mice in acetyl-CoA between WT and Ces1d−/− mice and to by acetyl-CoA and increased in Ces1d−/− studies lipogenic substrates that represent metabolism of In HSD leads to DNL and lipid accumulation in the evidence from and studies suggests that of carbohydrate is an in the development of including NAFLD. Our that ablation of Ces1d activity hepatic lipid and inhibition of the human ortholog, CES1, might represent a novel pharmacological target for prevention and treatment of NAFLD. The of and for lipid by University of for in the and Li for with hydrolase acetyl-CoA carboxylase AMP-activated protein kinase lipase carboxylesterase carbohydrate-responsive element-binding protein de novo lipogenesis high-sucrose diet lipase lipid nonalcoholic fatty liver disease carboxylase protein kinase stearoyl-CoA desaturase 1 triacylglycerol

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