Soat2 ties cholesterol metabolism to β-oxidation and glucose tolerance in male mice.
ACAT2
CIDEC
GLUT2
NAFLD
Soat2
atherosclerosis
cardiometabolic diseases
cholesteryl esters
insulin resistance
lipoproteins
triglycerides
Journal
Journal of internal medicine
ISSN: 1365-2796
Titre abrégé: J Intern Med
Pays: England
ID NLM: 8904841
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
pubmed:
5
1
2022
medline:
23
7
2022
entrez:
4
1
2022
Statut:
ppublish
Résumé
Sterol O-acyltransferase 2 (Soat2) encodes acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2), which synthesizes cholesteryl esters in hepatocytes and enterocytes fated either to storage or to secretion into nascent triglyceride-rich lipoproteins. We aimed to unravel the molecular mechanisms leading to reduced hepatic steatosis when Soat2 is depleted in mice. Soat2 Glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), oral glucose tolerance (OGTT), and insulin tolerance tests significantly improved in Soat2 Our data demonstrate that ACAT2-generated cholesteryl esters negatively affect the metabolic control by retaining TG in the liver and that genetic inhibition of Soat2 improves liver steatosis via partitioning of lipids into secretory (VLDL-TG) and oxidative (fatty acids) pathways.
Sections du résumé
BACKGROUND
Sterol O-acyltransferase 2 (Soat2) encodes acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2), which synthesizes cholesteryl esters in hepatocytes and enterocytes fated either to storage or to secretion into nascent triglyceride-rich lipoproteins.
OBJECTIVES
We aimed to unravel the molecular mechanisms leading to reduced hepatic steatosis when Soat2 is depleted in mice.
METHODS
Soat2
RESULTS
Glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), oral glucose tolerance (OGTT), and insulin tolerance tests significantly improved in Soat2
CONCLUSION
Our data demonstrate that ACAT2-generated cholesteryl esters negatively affect the metabolic control by retaining TG in the liver and that genetic inhibition of Soat2 improves liver steatosis via partitioning of lipids into secretory (VLDL-TG) and oxidative (fatty acids) pathways.
Substances chimiques
Cholesterol Esters
0
Insulins
0
Lipoproteins, VLDL
0
Triglycerides
0
Sterol O-Acyltransferase
EC 2.3.1.26
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
296-307Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Références
Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract. 2009;5:150-9.
Pramfalk C, Davis MA, Eriksson M, Rudel LL, Parini P. Control of ACAT2 liver expression by HNF1. J Lipid Res. 2005;46:1868-76.
Pramfalk C, Karlsson E, Groop L, Rudel LL, Angelin B, Eriksson M, et al. Control of ACAT2 liver expression by HNF4{alpha}: lesson from MODY1 patients. Arterioscler Thromb Vasc Biol. 2009;29:1235-41.
Pramfalk C, Eriksson M, Parini P. Cholesteryl esters and ACAT. Eur J Lipid Sci Tech. 2012;114:624-33.
Parini P, Davis M, Lada AT, Erickson SK, Wright TL, Gustafsson U, et al. ACAT2 is localized to hepatocytes and is the major cholesterol-esterifying enzyme in human liver. Circulation. 2004;110:2017-23.
Zhang J, Sawyer JK, Marshall SM, Kelley KL, Davis MA, Wilson MD, et al. Cholesterol esters (CE) derived from hepatic sterol O-acyltransferase 2 (SOAT2) are associated with more atherosclerosis than CE from intestinal SOAT2. Circ Res. 2014;115:826-33.
Willner EL, Tow B, Buhman KK, Wilson M, Sanan DA, Rudel LL, et al. Deficiency of acyl CoA:cholesterol acyltransferase 2 prevents atherosclerosis in apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A. 2003;100:1262-7.
Buhman KK, Accad M, Novak S, Choi RS, Wong JS, Hamilton RL, et al. Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med. 2000;6:1341-7.
Bell TA, 3rd, Brown JM, Graham MJ, Lemonidis KM, Crooke RM, Rudel LL. Liver-specific inhibition of acyl-coenzyme A:cholesterol acyltransferase 2 with antisense oligonucleotides limits atherosclerosis development in apolipoprotein B100-only low-density lipoprotein receptor−/− mice. Arterioscler Thromb Vasc Biol. 2006;26:1814-20.
Bell TA, 3rd, Kelley K, Wilson MD, Sawyer JK, Rudel LL. Dietary fat-induced alterations in atherosclerosis are abolished by ACAT2-deficiency in ApoB100 only, LDLr−/− mice. Arterioscler Thromb Vasc Biol. 2007;27:1396-402.
Ohshiro T, Matsuda D, Sakai K, Degirolamo C, Yagyu H, Rudel LL, et al. Pyripyropene A, an acyl-coenzyme A:cholesterol acyltransferase 2-selective inhibitor, attenuates hypercholesterolemia and atherosclerosis in murine models of hyperlipidemia. Arterioscler Thromb Vasc Biol. 2011;31:1108-15.
Alger HM, Brown JM, Sawyer JK, Kelley KL, Shah R, Wilson MD, et al. Inhibtion of acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) prevents dietary cholesterol associated steatosis by enhancing hepatic triglyceride mobilization. J Biol Chem. 2010;285:14267-74.
Ahmed O, Pramfalk C, Pedrelli M, Olin M, Steffensen KR, Eriksson M, et al. Genetic depletion of Soat2 diminishes hepatic steatosis via genes regulating de novo lipogenesis and by GLUT2 protein in female mice. Dig Liv Dis. 2019;51:1016-22.
Sun HY, Chen TY, Tan YC, Wang CH, Young KC. Sterol O-acyltransferase 2 chaperoned by apolipoprotein J facilitates hepatic lipid accumulation following viral and nutrient stresses. Commun Biol. 2021;4:564.
Pedrelli M, Davoodpour P, Degirolamo C, Gomaraschi M, Graham M, Ossoli A, et al. Hepatic ACAT2 knock down increases ABCA1 and modifies HDL metabolism in mice. PLoS One. 2014;9:e93552.
Parini P, Johansson L, Broijersen A, Angelin B, Rudling M. Lipoprotein profiles in plasma and interstitial fluid analyzed with an automated gel-filtration system. Eur J Clin Invest. 2006;36:98-104.
Joly-Amado A, Denis RGP, Castel J, Lacombe A, Cansell C, Rouch C, et al. Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning. EMBO J. 2012;31:4276-88.
Hodson L, Bickerton AS, McQuaid SE, Roberts R, Karpe F, Frayn KN, et al. The contribution of splanchnic fat to VLDL triglyceride is greater in insulin-resistant than insulin-sensitive men and women: studies in the postprandial state. Diabetes. 2007;56:2433-41.
Barrows BR, Parks EJ. Contributions of different fatty acid sources to very low-density lipoprotein-triacylglycerol in the fasted and fed states. J Clin Endocrinol Metab. 2006;91:1446-52.
Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J Clin Invest. 1995;95:158-66.
Picard F, Boivin A, Lalonde J, Deshaies Y. Resistance of adipose tissue lipoprotein lipase to insulin action in rats fed an obesity-promoting diet. Am J Physiol. 2002;282:E412-8.
Lawrence JC, Gower BA, Timothy Garvey W, Julian Munoz A, Darnell BE, Oster RA, et al. Relationship between insulin sensitivity and muscle lipids may differ with muscle group and ethnicity. Open Obes J. 2010;2:137-44.
Matsusue K, Kusakabe T, Noguchi T, Takiguchi S, Suzuki T, Yamano S, et al. Hepatic steatosis in leptin-deficient mice is promoted by the PPARgamma target gene Fsp27. Cell Metab. 2008;7:302-11.
Toh SY, Gong J, Du G, Li JZ, Yang S, Ye J, et al. Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of fsp27 deficient mice. PLoS One. 2008;3:e2890.
Korach-Andre M, Archer A, Gabbi C, Barros RP, Pedrelli M, Steffensen KR, et al. Liver X receptors regulate de novo lipogenesis in a tissue-specific manner in C57BL/6 female mice. Am J Physiol Endocrinol Metab. 2011;301:E210-22.
Korach-Andre M, Parini P, Larsson L, Arner A, Steffensen KR, Gustafsson JA. Separate and overlapping metabolic functions of LXRalpha and LXRbeta in C57Bl/6 female mice. Am J Physiol Endocrinol Metab. 2010;298:E167-78.
Parini P, Gustafsson U, Davis MA, Larsson L, Einarsson C, Wilson M, et al. Cholesterol synthesis inhibition elicits an integrated molecular response in human livers including decreased ACAT2. Arterioscler Thromb Vasc Biol. 2008;28:1200-6.
Pramfalk C, Parini P, Gustafsson U, Sahlin S, Eriksson M. Effects of high-dose statin on the human hepatic expression of genes involved in carbohydrate and triglyceride metabolism. J Intern Med. 2011;269:333-9.
Ahmed O, Littmann K, Gustafsson U, Pramfalk C, Öörni K, Larsson L, et al. Ezetimibe in combination with simvastatin reduces remnant cholesterol without affecting biliary lipid concentrations in gallstone patients. J Am Heart Assoc. 2018;7:e009876.
Melchior JT, Sawyer JK, Kelley KL, Shah R, Wilson MD, Hantgan RR, et al. LDL particle core enrichment in cholesteryl oleate increases proteoglycan binding and promotes atherosclerosis. J Lipid Res. 2013;54:2495-503.
Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res. 2016;118:547-63.
Marks J, Carvou NJ, Debnam ES, Srai SK, Unwin RJ. Diabetes increases facilitative glucose uptake and GLUT2 expression at the rat proximal tubule brush border membrane. J Physiol. 2003;553:137-45.
Narasimhan A, Chinnaiyan M, Karundevi B. Ferulic acid regulates hepatic GLUT2 gene expression in high fat and fructose-induced type-2 diabetic adult male rat. Eur J Pharmacol. 2015;761:391-7.
Im SS, Kang SY, Kim SY, Kim HI, Kim JW, Kim KS, et al. Glucose-stimulated upregulation of GLUT2 gene is mediated by sterol response element-binding protein-1c in the hepatocytes. Diabetes. 2005;54:1684-91.
Borglykke A, Grarup N, Sparsø T, Linneberg A, Fenger M, Jeppesen J, et al. Genetic variant SLC2A2 [corrected] is associated with risk of cardiovascular disease-assessing the individual and cumulative effect of 46 type 2 diabetes related genetic variants. PLoS One. 2012;7:e50418.
Igl W, Johansson A, Wilson JF, Wild SH, Polašek O, Hayward C, et al. Modeling of environmental effects in genome-wide association studies identifies SLC2A2 and HP as novel loci influencing serum cholesterol levels. PLoS Genet. 2010;6:e1000798.
Taha D, Al-Harbi N, Al-Sabban E. Hyperglycemia and hypoinsulinemia in patients with Fanconi-Bickel syndrome. J Pediatr Endocrinol Metab. 2008;21:581-6.
Ferre T, Riu E, Franckhauser S, Agudo J, Bosch F. Long-term overexpression of glucokinase in the liver of transgenic mice leads to insulin resistance. Diabetologia. 2003;46:1662-8.
Randle PJ. Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev. 1998;14:263-83.
Kim JY, Bacha F, Tfayli H, Michaliszyn SF, Yousuf S, Arslanian S. Adipose tissue insulin resistance in youth on the spectrum from normal weight to obese and from normal glucose tolerance to impaired glucose tolerance to type 2 diabetes. Diabetes Care. 2019;42:265-72.
Xu Y, Du X, Turner N, Brown AJ, Yang H. Enhanced acyl-CoA:cholesterol acyltransferase activity increases cholesterol levels on the lipid droplet surface and impairs adipocyte function. J Biol Chem. 2019;294:19306-21.
Tanaka N, Takahashi S, Matsubara T, Jiang C, Sakamoto W, Chanturiya T, et al. Adipocyte-specific disruption of fat-specific protein 27 causes hepatosteatosis and insulin resistance in high-fat diet-fed mice. J Biol Chem. 2015;290:3092-3105.
Zhou L, Park S-Y, Xu L, Xia X, Ye J, Su L, et al. Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice. Nat Commun. 2015:6: 5949.
Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple RK, Dash S, et al. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol Med. 2009;1:280-7.
Matsusue K, Kusakabe T, Noguchi T, Takiguchi S, Suzuki T, Yamano S, et al. Hepatic steatosis in leptin-deficient mice is promoted by the PPARgamma target gene Fsp27. Cell Metab. 2008;7:302-11.
Wang Y-J, Bian Y, Luo J, Lu M, Xiong Y, Guo S-Y, et al. Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation. Nat Cell Biol. 2017;19:808-19.