Hepatic Mediators of Lipid Metabolism and Ketogenesis: Focus on Fatty Liver and Diabetes

Gustavo    W.    Fernandes; Barbara    M. L. C.   Bocco
doi:10.2174/1573399816999201103141216
Abstract

Background: Diabetes mellitus (DM) is a chronic disorder that it is caused by the absence of insulin secretion due to the inability of the pancreas to produce it (type 1 diabetes; T1DM), or due to defects of insulin signaling in the peripheral tissues, resulting in insulin resistance (type 2 diabetes; T2DM). Commonly, the occurrence of insulin resistance in T2DM patients reflects the high prevalence of obesity and non-alcoholic fatty liver disease (NAFLD) in these individuals. In fact, approximately 60% of T2DM patients are also diagnosed to have NAFLD, and this condition is strongly linked with insulin resistance and obesity. NAFLD is the hepatic manifestation of obesity and metabolic syndrome and includes a spectrum of pathological conditions, which range from simple steatosis (NAFL), non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. NAFLD manifestation is followed by a series of hepatic lipid deregulations and the main abnormalities are increased triglyceride levels, increased hepatic production of VLDL and a reduction in VLDL catabolism. During the progression of NAFLD, the production of ketone bodies progressively reduces while hepatic glucose synthesis and output increases. In fact, most of the fat that enters the liver can be disposed of through ketogenesis, preventing the development of NAFLD and hyperglycemia.
Objective: This review will focus on the pathophysiological aspect of hepatic lipid metabolism deregulation, ketogenesis, and its relevance in the progression of NAFLD and T2DM.
Conclusion: A better understanding of the molecular mediators involved in lipid synthesis and ketogenesis can lead to new treatments for metabolic disorders in the liver, such as NAFLD.
Keywords: Type 2 diabetes, steatosis, NAFLD ketogenesis, lipid metabolism, steatohepatitis.
[1] 
Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clinic proceedings Mayo Clinic  1980; 55(7): 434-8.
[2] 
Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol  2013; 10(11): 686-90.
[http://dx.doi.org/10.1038/nrgastro.2013.171] [PMID: 24042449] 
[3] 
Xia MF, Bian H, Gao X. NAFLD and Diabetes: Two Sides of the Same Coin? Rationale for Gene-Based Personalized NAFLD Treatment. Front Pharmacol  2019; 10: 877.
[http://dx.doi.org/10.3389/fphar.2019.00877] [PMID: 31447675] 
[4] 
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest  2005; 115(5): 1343-51.
[http://dx.doi.org/10.1172/JCI23621] [PMID: 15864352] 
[5] 
Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology  2014; 146(3): 726-35.
[http://dx.doi.org/10.1053/j.gastro.2013.11.049] [PMID: 24316260] 
[6] 
Sunny NE, Parks EJ, Browning JD, Burgess SC. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab  2011; 14(6): 804-10.
[http://dx.doi.org/10.1016/j.cmet.2011.11.004] [PMID: 22152305] 
[7] 
Fletcher JA, Deja S, Satapati S, Fu X, Burgess SC, Browning JD. Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver. JCI Insight  2019; 5: 5.
[http://dx.doi.org/10.1172/jci.insight.127737] [PMID: 31012869] 
[8] 
Reddy JK, Mannaerts GP. Peroxisomal lipid metabolism. Annu Rev Nutr  1994; 14: 343-70.
[http://dx.doi.org/10.1146/annurev.nu.14.070194.002015] [PMID: 7946524] 
[9] 
Iozzo P, Bucci M, Roivainen A, Nagren K, Jarvisalo MJ, Kiss J, et al. Fatty acid metabolism in the liver, measured by positron emission tomography, is increased in obese individuals. Gastroenterology  2010; 139(3): 846-56.
[http://dx.doi.org/10.1053/j.gastro.2010.05.039] 
[10] 
Brundin T, Thörne A, Wahren J. Heat leakage across the abdominal wall and meal-induced thermogenesis in normal-weight and obese subjects. Metabolism  1992; 41(1): 49-55.
[http://dx.doi.org/10.1016/0026-0495(92)90190-L] [PMID: 1531691] 
[11] 
Cotter DG, Ercal B, Huang X, et al. Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia. J Clin Invest  2014; 124(12): 5175-90.
[http://dx.doi.org/10.1172/JCI76388] [PMID: 25347470] 
[12] 
Blair M. Diabetes Mellitus Review. Urol Nurs  2016; 36(1): 27-36.
[http://dx.doi.org/10.7257/1053-816X.2016.36.1.27] [PMID: 27093761] 
[13] 
DeFronzo RA, Ferrannini E, Groop L, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers  2015; 1: 15019.
[http://dx.doi.org/10.1038/nrdp.2015.19] [PMID: 27189025] 
[14] 
Olokoba AB, Obateru OA, Olokoba LB. Type 2 diabetes mellitus: a review of current trends. Oman Med J  2012; 27(4): 269-73.
[http://dx.doi.org/10.5001/omj.2012.68] [PMID: 23071876] 
[15] 
Kharroubi AT, Darwish HM. Diabetes mellitus: The epidemic of the century. World J Diabetes  2015; 6(6): 850-67.
[http://dx.doi.org/10.4239/wjd.v6.i6.850] [PMID: 26131326] 
[16] 
Craig ME, Jefferies C, Dabelea D, Balde N, Seth A, Donaghue KC. International Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2014. Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes  2014; 15(Suppl. 20): 4-17.
[http://dx.doi.org/10.1111/pedi.12186] [PMID: 25182305] 
[17] 
Dabelea D, Mayer-Davis EJ, Saydah S, et al. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA  2014; 311(17): 1778-86.
[http://dx.doi.org/10.1001/jama.2014.3201] [PMID: 24794371] 
[18] 
Devendra D, Liu E, Eisenbarth GS. Type 1 diabetes: recent developments. BMJ  2004; 328(7442): 750-4.
[http://dx.doi.org/10.1136/bmj.328.7442.750] [PMID: 15044291] 
[19] 
Donath MY, Ehses JA, Maedler K, et al. Mechanisms of beta-cell death in type 2 diabetes. Diabetes  2005; 54(Suppl. 2): S108-13.
[http://dx.doi.org/10.2337/diabetes.54.suppl_2.S108] [PMID: 16306327] 
[20] 
Gestational diabetes mellitus. Nat Rev Dis Primers  2019; 5(1): 48.
[http://dx.doi.org/10.1038/s41572-019-0104-1] [PMID: 31296868] 
[21] 
Hollander MH, Paarlberg KM, Huisjes AJ. Gestational diabetes: a review of the current literature and guidelines. Obstet Gynecol Surv  2007; 62(2): 125-36.
[http://dx.doi.org/10.1097/01.ogx.0000253303.92229.59] [PMID: 17229329] 
[22] 
Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol  2017; 14(1): 32-42.
[http://dx.doi.org/10.1038/nrgastro.2016.147] [PMID: 27729660] 
[23] 
Hazlehurst JM, Woods C, Marjot T, Cobbold JF, Tomlinson JW. Non-alcoholic fatty liver disease and diabetes. Metabolism  2016; 65(8): 1096-108.
[http://dx.doi.org/10.1016/j.metabol.2016.01.001] [PMID: 26856933] 
[24] 
Ballestri S, Zona S, Targher G, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol  2016; 31(5): 936-44.
[http://dx.doi.org/10.1111/jgh.13264] [PMID: 26667191] 
[25] 
Rector RS, Thyfault JP, Wei Y, Ibdah JA. Non-alcoholic fatty liver disease and the metabolic syndrome: an update. World J Gastroenterol  2008; 14(2): 185-92.
[http://dx.doi.org/10.3748/wjg.14.185] [PMID: 18186553] 
[26] 
Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol  2006; 40(Suppl. 1): S5-S10.
[PMID: 16540768] 
[27] 
Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes  2001; 50(8): 1844-50.
[http://dx.doi.org/10.2337/diabetes.50.8.1844] [PMID: 11473047] 
[28] 
Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology  2003; 37(5): 1202-19.
[http://dx.doi.org/10.1053/jhep.2003.50193] [PMID: 12717402] 
[29] 
Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med  1999; 107(5): 450-5.
[http://dx.doi.org/10.1016/S0002-9343(99)00271-5] [PMID: 10569299] 
[30] 
Fon Tacer K, Rozman D. Nonalcoholic Fatty liver disease: focus on lipoprotein and lipid deregulation. J Lipids  2011; 2011: 783976.
[http://dx.doi.org/10.1155/2011/783976] [PMID: 21773052] 
[31] 
Haas JT, Francque S, Staels B. Pathophysiology and Mechanisms of nonalcoholic fatty liver disease. Annu Rev Physiol  2016; 78: 181-205.
[http://dx.doi.org/10.1146/annurev-physiol-021115-105331] [PMID: 26667070] 
[32] 
Perry RJ, Camporez JG, Kursawe R, et al. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell  2015; 160(4): 745-58.
[http://dx.doi.org/10.1016/j.cell.2015.01.012] [PMID: 25662011] 
[33] 
Jensen TL, Kiersgaard MK, Sørensen DB, Mikkelsen LF. Fasting of mice: a review. Lab Anim  2013; 47(4): 225-40.
[http://dx.doi.org/10.1177/0023677213501659] [PMID: 24025567] 
[34] 
Cali AM, Zern TL, Taksali SE, et al. Intrahepatic fat accumulation and alterations in lipoprotein composition in obese adolescents: a perfect proatherogenic state. Diabetes Care  2007; 30(12): 3093-8.
[http://dx.doi.org/10.2337/dc07-1088] [PMID: 17717283] 
[35] 
Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest  2004; 114(2): 147-52.
[http://dx.doi.org/10.1172/JCI200422422] [PMID: 15254578] 
[36] 
Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology  1998; 114(4): 842-5.
[http://dx.doi.org/10.1016/S0016-5085(98)70599-2] [PMID: 9547102] 
[37] 
Anstee QM, McPherson S, Day CP. How big a problem is non-alcoholic fatty liver disease? BMJ  2011; 343: d3897.
[http://dx.doi.org/10.1136/bmj.d3897] [PMID: 21768191] 
[38] 
Arguello G, Balboa E, Arrese M, Zanlungo S. Recent insights on the role of cholesterol in non-alcoholic fatty liver disease. Biochim Biophys Acta  2015; 1852(9): 1765-78.
[http://dx.doi.org/10.1016/j.bbadis.2015.05.015] [PMID: 26027904] 
[39] 
Lonardo A, Byrne CD, Caldwell SH, Cortez-Pinto H, Targher G. Global epidemiology of nonalcoholic fatty liver disease: Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology  2016; 64(4): 1388-9.
[http://dx.doi.org/10.1002/hep.28584] [PMID: 27038241] 
[40] 
Younossi ZM. Non-alcoholic fatty liver disease - A global public health perspective. J Hepatol  2019; 70(3): 531-44.
[http://dx.doi.org/10.1016/j.jhep.2018.10.033] [PMID: 30414863] 
[41] 
Goessling W, Massaro JM, Vasan RS, D’Agostino RB Sr, Ellison RC, Fox CS. Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology  2008; 135(6): 1935-1944, 1944.e1.
[http://dx.doi.org/10.1053/j.gastro.2008.09.018] [PMID: 19010326] 
[42] 
Kunutsor SK, Apekey TA, Walley J. Liver aminotransferases and risk of incident type 2 diabetes: a systematic review and meta-analysis. Am J Epidemiol  2013; 178(2): 159-71.
[http://dx.doi.org/10.1093/aje/kws469] [PMID: 23729682] 
[43] 
Bae JC, Rhee EJ, Lee WY, et al. Combined effect of nonalcoholic fatty liver disease and impaired fasting glucose on the development of type 2 diabetes: a 4-year retrospective longitudinal study. Diabetes Care  2011; 34(3): 727-9.
[http://dx.doi.org/10.2337/dc10-1991] [PMID: 21278140] 
[44] 
Armstrong MJ, Adams LA, Canbay A, Syn WK. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology  2014; 59(3): 1174-97.
[http://dx.doi.org/10.1002/hep.26717] [PMID: 24002776] 
[45] 
Portillo-Sanchez P, Bril F, Maximos M, et al. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab  2015; 100(6): 2231-8.
[http://dx.doi.org/10.1210/jc.2015-1966] [PMID: 25885947] 
[46] 
Wang C, Wang X, Gong G, Ben Q, Qiu W, Chen Y, et al. Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: A systematic review and meta-analysis of cohort studies. Int J canc  2012; 130(7): 1639-48.
[http://dx.doi.org/10.1002/ijc.26165] 
[47] 
Koehler EM, Plompen EP, Schouten JN, et al. Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: The Rotterdam study. Hepatology  2016; 63(1): 138-47.
[http://dx.doi.org/10.1002/hep.27981] [PMID: 26171685] 
[48] 
Kwok R, Choi KC, Wong GL, et al. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut  2016; 65(8): 1359-68.
[http://dx.doi.org/10.1136/gutjnl-2015-309265] [PMID: 25873639] 
[49] 
El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology  2004; 126(2): 460-8.
[http://dx.doi.org/10.1053/j.gastro.2003.10.065] [PMID: 14762783] 
[50] 
Sanyal A, Poklepovic A, Moyneur E, Barghout V. Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin  2010; 26(9): 2183-91.
[http://dx.doi.org/10.1185/03007995.2010.506375] [PMID: 20666689] 
[51] 
Lomonaco R, Bril F, Portillo-Sanchez P, et al. Metabolic Impact of Nonalcoholic Steatohepatitis in Obese Patients With Type 2 Diabetes. Diabetes Care  2016; 39(4): 632-8.
[http://dx.doi.org/10.2337/dc15-1876] [PMID: 26861926] 
[52] 
Radaelli MG, Martucci F, Perra S, et al. NAFLD/NASH in patients with type 2 diabetes and related treatment options. J Endocrinol Invest  2018; 41(5): 509-21.
[http://dx.doi.org/10.1007/s40618-017-0799-3] [PMID: 29189999] 
[53] 
Jelenik T, Kaul K, Séquaris G, et al. Mechanisms of insulin resistance in primary and secondary nonalcoholic fatty liver. Diabetes  2017; 66(8): 2241-53.
[http://dx.doi.org/10.2337/db16-1147] [PMID: 28490610] 
[54] 
Utzschneider KM, Kahn SE. Review: The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab  2006; 91(12): 4753-61.
[http://dx.doi.org/10.1210/jc.2006-0587] [PMID: 16968800] 
[55] 
Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology  2001; 120(5): 1183-92.
[http://dx.doi.org/10.1053/gast.2001.23256] [PMID: 11266382] 
[56] 
Lomonaco R, Ortiz-Lopez C, Orsak B, et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology  2012; 55(5): 1389-97.
[http://dx.doi.org/10.1002/hep.25539] [PMID: 22183689] 
[57] 
Wilson CG, Tran JL, Erion DM, Vera NB, Febbraio M, Weiss EJ. Hepatocyte-specific disruption of cd36 attenuates fatty liver and improves insulin sensitivity in HFD-Fed mice. Endocrinology  2016; 157(2): 570-85.
[http://dx.doi.org/10.1210/en.2015-1866] [PMID: 26650570] 
[58] 
Zhu L, Baker SS, Liu W, et al. Lipid in the livers of adolescents with nonalcoholic steatohepatitis: combined effects of pathways on steatosis. Metabolism  2011; 60(7): 1001-11.
[http://dx.doi.org/10.1016/j.metabol.2010.10.003] [PMID: 21075404] 
[59] 
Larter CZ, Yeh MM, Van Rooyen DM, et al. Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice. J Gastroenterol Hepatol  2009; 24(10): 1658-68.
[http://dx.doi.org/10.1111/j.1440-1746.2009.05996.x] [PMID: 19788606] 
[60] 
Alkhatatbeh MJ, Enjeti AK, Acharya S, Thorne RF, Lincz LF. The origin of circulating CD36 in type 2 diabetes. Nutr Diabetes  2013; 3: e59.
[http://dx.doi.org/10.1038/nutd.2013.1] [PMID: 23381664] 
[61] 
Smith GI, Shankaran M, Yoshino M, et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest  2020; 130(3): 1453-60.
[http://dx.doi.org/10.1172/JCI134165] [PMID: 31805015] 
[62] 
Paglialunga S, Dehn CA. Clinical assessment of hepatic de novo lipogenesis in non-alcoholic fatty liver disease. Lipids Health Dis  2016; 15(1): 159.
[http://dx.doi.org/10.1186/s12944-016-0321-5] [PMID: 27640119] 
[63] 
Eissing L, Scherer T, Tödter K, et al. De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health. Nat Commun  2013; 4: 1528.
[http://dx.doi.org/10.1038/ncomms2537] [PMID: 23443556] 
[64] 
Ferré P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab  2010; 12(Suppl. 2): 83-92.
[http://dx.doi.org/10.1111/j.1463-1326.2010.01275.x] [PMID: 21029304] 
[65] 
Wang Y, Viscarra J, Kim SJ, Sul HS. Transcriptional regulation of hepatic lipogenesis. Nat Rev Mol Cell Biol  2015; 16(11): 678-89.
[http://dx.doi.org/10.1038/nrm4074] [PMID: 26490400] 
[66] 
Shimano H, Horton JD, Shimomura I, Hammer RE, Brown MS, Goldstein JL. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest  1997; 99(5): 846-54.
[http://dx.doi.org/10.1172/JCI119248] [PMID: 9062341] 
[67] 
Yahagi N, Shimano H, Hasty AH, et al. Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice. J Biol Chem  2002; 277(22): 19353-7.
[http://dx.doi.org/10.1074/jbc.M201584200] [PMID: 11923308] 
[68] 
Shimomura I, Bashmakov Y, Horton JD. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem  1999; 274(42): 30028-32.
[http://dx.doi.org/10.1074/jbc.274.42.30028] [PMID: 10514488] 
[69] 
Sanders FW, Griffin JL. De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose. Biol Rev Camb Philos Soc  2016; 91(2): 452-68.
[http://dx.doi.org/10.1111/brv.12178] [PMID: 25740151] 
[70] 
Hodson L, Gunn PJ. The regulation of hepatic fatty acid synthesis and partitioning: the effect of nutritional state. Nat Rev Endocrinol  2019; 15(12): 689-700.
[http://dx.doi.org/10.1038/s41574-019-0256-9] [PMID: 31554932] 
[71] 
Horton JD, Shah NA, Warrington JA, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA  2003; 100(21): 12027-32.
[http://dx.doi.org/10.1073/pnas.1534923100] [PMID: 14512514] 
[72] 
McGarry JD, Mannaerts GP, Foster DW. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest  1977; 60(1): 265-70.
[http://dx.doi.org/10.1172/JCI108764] [PMID: 874089] 
[73] 
Huang YY, Gusdon AM, Qu S. Nonalcoholic fatty liver disease: molecular pathways and therapeutic strategies. Lipids Health Dis  2013; 12: 171.
[http://dx.doi.org/10.1186/1476-511X-12-171] [PMID: 24209497] 
[74] 
Kim T, He L, Johnson MS, et al. Carnitine palmitoyltransferase 1b deficiency protects mice from diet-induced insulin resistance. J Diabetes Metab  2014; 5(4): 361.
[PMID: 25309812] 
[75] 
Conti R, Mannucci E, Pessotto P, et al. Selective reversible inhibition of liver carnitine palmitoyl-transferase 1 by teglicar reduces gluconeogenesis and improves glucose homeostasis. Diabetes  2011; 60(2): 644-51.
[http://dx.doi.org/10.2337/db10-0346] [PMID: 21270274] 
[76] 
Koliaki C, Szendroedi J, Kaul K, et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab  2015; 21(5): 739-46.
[http://dx.doi.org/10.1016/j.cmet.2015.04.004] [PMID: 25955209] 
[77] 
Dentin R, Benhamed F, Hainault I, et al. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes  2006; 55(8): 2159-70.
[http://dx.doi.org/10.2337/db06-0200] [PMID: 16873678] 
[78] 
Kursawe R, Caprio S, Giannini C, et al. Decreased transcription of ChREBP-α/β isoforms in abdominal subcutaneous adipose tissue of obese adolescents with prediabetes or early type 2 diabetes: associations with insulin resistance and hyperglycemia. Diabetes  2013; 62(3): 837-44.
[http://dx.doi.org/10.2337/db12-0889] [PMID: 23209190] 
[79] 
Uyeda K, Yamashita H, Kawaguchi T. Carbohydrate responsive element-binding protein (ChREBP): a key regulator of glucose metabolism and fat storage. Biochem Pharmacol  2002; 63(12): 2075-80.
[http://dx.doi.org/10.1016/S0006-2952(02)01012-2] [PMID: 12110366] 
[80] 
Yamashita H, Takenoshita M, Sakurai M, et al. A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver. Proc Natl Acad Sci USA  2001; 98(16): 9116-21.
[http://dx.doi.org/10.1073/pnas.161284298] [PMID: 11470916] 
[81] 
Wang H, Chu W, Das SK, Ren Q, Hasstedt SJ, Elbein SC. Liver pyruvate kinase polymorphisms are associated with type 2 diabetes in northern European Caucasians. Diabetes  2002; 51(9): 2861-5.
[http://dx.doi.org/10.2337/diabetes.51.9.2861] [PMID: 12196482] 
[82] 
Matsuda T, Noguchi T, Takenaka M, Yamada K, Tanaka T. Regulation of L-type pyruvate kinase gene expression by dietary fructose in normal and diabetic rats. J Biochem  1990; 107(4): 655-60.
[http://dx.doi.org/10.1093/oxfordjournals.jbchem.a123103] [PMID: 2193023] 
[83] 
Munnich A, Lyonnet S, Chauvet D, Van Schaftingen E, Kahn A. Differential effects of glucose and fructose on liver L-type pyruvate kinase gene expression in vivo. J Biol Chem  1987; 262(35): 17065-71.
[PMID: 2824512] 
[84] 
Dorn C, Riener MO, Kirovski G, et al. Expression of fatty acid synthase in nonalcoholic fatty liver disease. Int J Clin Exp Pathol  2010; 3(5): 505-14.
[PMID: 20606731] 
[85] 
Fonseca TL, Fernandes GW, McAninch EA, et al. Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity. Proc Natl Acad Sci USA  2015; 112(45): 14018-23.
[http://dx.doi.org/10.1073/pnas.1508943112] [PMID: 26508642] 
[86] 
Perfield JW II, Ortinau LC, Pickering RT, Ruebel ML, Meers GM, Rector RS. Altered hepatic lipid metabolism contributes to nonalcoholic fatty liver disease in leptin-deficient Ob/Ob mice. J Obes  2013; 2013: 296537.
[http://dx.doi.org/10.1155/2013/296537] [PMID: 23401753] 
[87] 
Menendez JA, Vazquez-Martin A, Ortega FJ, Fernandez-Real JM. Fatty acid synthase: association with insulin resistance, type 2 diabetes, and cancer. Clin Chem  2009; 55(3): 425-38.
[http://dx.doi.org/10.1373/clinchem.2008.115352] [PMID: 19181734] 
[88] 
Peet DJ, Janowski BA, Mangelsdorf DJ. The LXRs: a new class of oxysterol receptors. Curr Opin Genet Dev  1998; 8(5): 571-5.
[http://dx.doi.org/10.1016/S0959-437X(98)80013-0] [PMID: 9794827] 
[89] 
Repa JJ, Mangelsdorf DJ. The liver X receptor gene team: potential new players in atherosclerosis. Nat Med  2002; 8(11): 1243-8.
[http://dx.doi.org/10.1038/nm1102-1243] [PMID: 12411951] 
[90] 
Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev  1995; 9(9): 1033-45.
[http://dx.doi.org/10.1101/gad.9.9.1033] [PMID: 7744246] 
[91] 
Peet DJ, Turley SD, Ma W, et al. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell  1998; 93(5): 693-704.
[http://dx.doi.org/10.1016/S0092-8674(00)81432-4] [PMID: 9630215] 
[92] 
Moreau A, Téruel C, Beylot M, et al. A novel pregnane X receptor and S14-mediated lipogenic pathway in human hepatocyte. Hepatology  2009; 49(6): 2068-79.
[http://dx.doi.org/10.1002/hep.22907] [PMID: 19437491] 
[93] 
Ghoneim RH, Ngo Sock ET, Lavoie JM, Piquette-Miller M. Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition. Br J Nutr  2015; 113(3): 507-16.
[http://dx.doi.org/10.1017/S0007114514003717] [PMID: 25612518] 
[94] 
Zhou J, Febbraio M, Wada T, et al. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology  2008; 134(2): 556-67.
[http://dx.doi.org/10.1053/j.gastro.2007.11.037] [PMID: 18242221] 
[95] 
Cao G, Liang Y, Broderick CL, et al. Antidiabetic action of a liver x receptor agonist mediated by inhibition of hepatic gluconeogenesis. J Biol Chem  2003; 278(2): 1131-6.
[http://dx.doi.org/10.1074/jbc.M210208200] [PMID: 12414791] 
[96] 
Alves-Bezerra M, Cohen DE. Triglyceride Metabolism in the Liver. Compr Physiol  2017; 8(1): 1-8.
[PMID: 29357123] 
[97] 
Mota M, Banini BA, Cazanave SC, Sanyal AJ. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism  2016; 65(8): 1049-61.
[http://dx.doi.org/10.1016/j.metabol.2016.02.014] [PMID: 26997538] 
[98] 
Kawano Y, Cohen DE. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J Gastroenterol  2013; 48(4): 434-41.
[http://dx.doi.org/10.1007/s00535-013-0758-5] [PMID: 23397118] 
[99] 
Cortés VA, Curtis DE, Sukumaran S, et al. Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy. Cell Metab  2009; 9(2): 165-76.
[http://dx.doi.org/10.1016/j.cmet.2009.01.002] [PMID: 19187773] 
[100] 
Thuresson ER. Inhibition of glycerol-3-phosphate acyltransferase as a potential treatment for insulin resistance and type 2 diabetes. Curr Opin Investig Drugs  2004; 5(4): 411-8.
[PMID: 15134282] 
[101] 
Kajimoto K, Suemitsu E, Sato Y, Sakurai Y, Harashima H. Liver-specific silencing of lipin1 reduces fat mass as well as hepatic triglyceride biosynthesis in mice. Biol Pharm Bull  2016; 39(10): 1653-61.
[http://dx.doi.org/10.1248/bpb.b16-00353] [PMID: 27725442] 
[102] 
Bhatt-Wessel B, Jordan TW, Miller JH, Peng L. Role of DGAT enzymes in triacylglycerol metabolism. Arch Biochem Biophys  2018; 655: 1-11.
[http://dx.doi.org/10.1016/j.abb.2018.08.001] [PMID: 30077544] 
[103] 
Choi CS, Savage DB, Kulkarni A, et al. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem  2007; 282(31): 22678-88.
[http://dx.doi.org/10.1074/jbc.M704213200] [PMID: 17526931] 
[104] 
Yu XX, Murray SF, Pandey SK, et al. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology  2005; 42(2): 362-71.
[http://dx.doi.org/10.1002/hep.20783] [PMID: 16001399] 
[105] 
Yamaguchi K, Yang L, McCall S, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology  2007; 45(6): 1366-74.
[http://dx.doi.org/10.1002/hep.21655] [PMID: 17476695] 
[106] 
Subauste A, Burant CF. DGAT: novel therapeutic target for obesity and type 2 diabetes mellitus. Curr Drug Targets Immune Endocr Metabol Disord  2003; 3(4): 263-70.
[http://dx.doi.org/10.2174/1568008033340081] [PMID: 14683457] 
[107] 
Shelness GS, Sellers JA. Very-low-density lipoprotein assembly and secretion. Curr Opin Lipidol  2001; 12(2): 151-7.
[http://dx.doi.org/10.1097/00041433-200104000-00008] [PMID: 11264986] 
[108] 
Adiels M, Olofsson SO, Taskinen MR, Borén J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol  2008; 28(7): 1225-36.
[http://dx.doi.org/10.1161/ATVBAHA.107.160192] [PMID: 18565848] 
[109] 
Haidari M, Leung N, Mahbub F, et al. Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoB48-containing lipoprotein overproduction. J Biol Chem  2002; 277(35): 31646-55.
[http://dx.doi.org/10.1074/jbc.M200544200] [PMID: 12070142] 
[110] 
Au WS, Kung HF, Lin MC. Regulation of microsomal triglyceride transfer protein gene by insulin in HepG2 cells: roles of MAPKerk and MAPKp38. Diabetes  2003; 52(5): 1073-80.
[http://dx.doi.org/10.2337/diabetes.52.5.1073] [PMID: 12716735] 
[111] 
McGarry JD, Foster DW. Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem  1980; 49: 395-420.
[http://dx.doi.org/10.1146/annurev.bi.49.070180.002143] [PMID: 6157353] 
[112] 
Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab  2014; 25(1): 42-52.
[http://dx.doi.org/10.1016/j.tem.2013.09.002] [PMID: 24140022] 
[113] 
Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab  2017; 25(2): 262-84.
[http://dx.doi.org/10.1016/j.cmet.2016.12.022] [PMID: 28178565] 
[114] 
Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev  1999; 15(6): 412-26.
[http://dx.doi.org/10.1002/(SICI)1520-7560(199911/12)15:6<412::AID-DMRR72>3.0.CO;2-8] [PMID: 10634967] 
[115] 
Owen OE, Trapp VE, Skutches CL, et al. Acetone metabolism during diabetic ketoacidosis. Diabetes  1982; 31(3): 242-8.
[http://dx.doi.org/10.2337/diab.31.3.242] [PMID: 6818074] 
[116] 
Tanda N, Hinokio Y, Washio J, Takahashi N, Koseki T, Eds. Breath acetone in type 1 and type 2 diabetes mellitus. Tokyo: Springer Japan 2012.
[http://dx.doi.org/10.1007/978-4-431-54070-0_59] 
[117] 
Jain SK, Kannan K, Lim G. Ketosis (acetoacetate) can generate oxygen radicals and cause increased lipid peroxidation and growth inhibition in human endothelial cells. Free Radic Biol Med  1998; 25(9): 1083-8.
[http://dx.doi.org/10.1016/S0891-5849(98)00140-3] [PMID: 9870562] 
[118] 
Jain SK, McVie R, Jaramillo JJ, Chen Y. Hyperketonemia (acetoacetate) increases the oxidizability of LDL + VLDL in Type-I diabetic patients. Free Radic Biol Med  1998; 24(1): 175-81.
[http://dx.doi.org/10.1016/S0891-5849(97)00213-X] [PMID: 9436628] 
[119] 
Huang LH, Melton EM, Li H, et al. Myeloid-specific Acat1 ablation attenuates inflammatory responses in macrophages, improves insulin sensitivity, and suppresses diet-induced obesity. Am J Physiol Endocrinol Metab  2018; 315(3): E340-56.
[http://dx.doi.org/10.1152/ajpendo.00174.2017] [PMID: 29533741] 
[120] 
Shibuya* HSaK. An ACAT-1Inhibitor, K-604, Ameliorates Hepatic Inflammation in NAFLD and NASH Models. J Gastroenterol Pancreatol Liver Disord 2016.
[121] 
Serra D, Casals N, Asins G, Royo T, Ciudad CJ, Hegardt FG. Regulation of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase protein by starvation, fat feeding, and diabetes. Arch Biochem Biophys  1993; 307(1): 40-5.
[http://dx.doi.org/10.1006/abbi.1993.1557] [PMID: 7902069] 
[122] 
Shukla SK, Liu W, Sikder K, et al. HMGCS2 is a key ketogenic enzyme potentially involved in type 1 diabetes with high cardiovascular risk. Sci Rep  2017; 7(1): 4590.
[http://dx.doi.org/10.1038/s41598-017-04469-z] [PMID: 28676675] 
[123] 
Geisler CE, Ghimire S, Bogan RL, Renquist BJ. Role of ketone signaling in the hepatic response to fasting. Am J Physiol Gastrointest Liver Physiol  2019; 316(5): G623-31.
[http://dx.doi.org/10.1152/ajpgi.00415.2017] [PMID: 30767679] 
[124] 
Otsuka H, Kimura T, Ago Y, et al. Deficiency of 3-hydroxybutyrate dehydrogenase (BDH1) in mice causes low ketone body levels and fatty liver during fasting. J Inherit Metab Dis  2020; 43(5): 960-8.
[http://dx.doi.org/10.1002/jimd.12243] [PMID: 32279332] 
[125] 
Gao Z, Yin J, Zhang J, et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes  2009; 58(7): 1509-17.
[http://dx.doi.org/10.2337/db08-1637] [PMID: 19366864] 
[126] 
Bhaskara S, Knutson SK, Jiang G, et al. Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell  2010; 18(5): 436-47.
[http://dx.doi.org/10.1016/j.ccr.2010.10.022] [PMID: 21075309] 
[127] 
Knutson SK, Chyla BJ, Amann JM, Bhaskara S, Huppert SS, Hiebert SW. Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J  2008; 27(7): 1017-28.
[http://dx.doi.org/10.1038/emboj.2008.51] [PMID: 18354499] 
[128] 
Mihaylova MM, Vasquez DS, Ravnskjaer K, et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell  2011; 145(4): 607-21.
[http://dx.doi.org/10.1016/j.cell.2011.03.043] [PMID: 21565617] 
[129] 
Galmozzi A, Mitro N, Ferrari A, et al. Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue. Diabetes  2013; 62(3): 732-42.
[http://dx.doi.org/10.2337/db12-0548] [PMID: 23069623] 
[130] 
Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res  2010; 107(9): 1058-70.
[http://dx.doi.org/10.1161/CIRCRESAHA.110.223545] [PMID: 21030723] 
[131] 
Shimazu T, Hirschey MD, Newman J, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science  2013; 339(6116): 211-4.
[http://dx.doi.org/10.1126/science.1227166] [PMID: 23223453] 
[132] 
Advani A, Huang Q, Thai K, et al. Long-term administration of the histone deacetylase inhibitor vorinostat attenuates renal injury in experimental diabetes through an endothelial nitric oxide synthase-dependent mechanism. Am J Pathol  2011; 178(5): 2205-14.
[http://dx.doi.org/10.1016/j.ajpath.2011.01.044] [PMID: 21514434] 
[133] 
Regnell SE, Lernmark Å. Hepatic steatosis in type 1 diabetes. Rev Diabet Stud  2011; 8(4): 454-67.
[http://dx.doi.org/10.1900/RDS.2011.8.454] [PMID: 22580727] 
[134] 
Bank IM, Shemie SD, Rosenblatt B, Bernard C, Mackie AS. Sudden cardiac death in association with the ketogenic diet. Pediatr Neurol  2008; 39(6): 429-31.
[http://dx.doi.org/10.1016/j.pediatrneurol.2008.08.013] [PMID: 19027591] 
[135] 
Bai F, Jiang FF, Lu JJ, et al. The impact of hyperglycemic emergencies on the kidney and liver. J Diabetes Res  2013; 2013: 967097.
[http://dx.doi.org/10.1155/2013/967097] [PMID: 24282823] 
[136] 
Garcia E, Shalaurova I, Matyus SP, et al. Ketone bodies are mildly elevated in subjects with type 2 diabetes mellitus and are inversely associated with insulin resistance as measured by the lipoprotein insulin resistance index. J Clin Med  2020; 9(2): E321.
[http://dx.doi.org/10.3390/jcm9020321] [PMID: 31979327] 
[137] 
Lu H, Hu F, Zeng Y, et al. Ketosis onset type 2 diabetes had better islet β-cell function and more serious insulin resistance. J Diabetes Res  2014; 2014: 510643.
[http://dx.doi.org/10.1155/2014/510643] [PMID: 24829925] 
[138] 
Garbow JR, Doherty JM, Schugar RC, et al. Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. Am J Physiol Gastrointest Liver Physiol  2011; 300(6): G956-67.
[http://dx.doi.org/10.1152/ajpgi.00539.2010] [PMID: 21454445] 
[139] 
Schugar RC, Crawford PA. Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care  2012; 15(4): 374-80.
[http://dx.doi.org/10.1097/MCO.0b013e3283547157] [PMID: 22617564] 
[140] 
Williamson JR, Wright PH, Malaisse WJ, Ashmore J. Control of gluconeogenesis by acetyl CoA in rats treated with glucagon and anti-insulin serum. Biochem Biophys Res Commun  1966; 24(5): 765-70.
[http://dx.doi.org/10.1016/0006-291X(66)90391-3] [PMID: 5970510] 
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DOI https://dx.doi.org/10.2174/1573399816999201103141216	Print ISSN 1573-3998
Publisher Name Bentham Science Publisher	Online ISSN 1875-6417
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