Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011;332:1519–23.
PubMed
Article
CAS
Google Scholar
Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 2010;51:1820–32.
PubMed
Article
Google Scholar
Adams LA, Waters OR, Knuiman MW, Elliott RR, Olynyk JK. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol. 2009;104:861–7.
PubMed
Article
Google Scholar
Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis. 2008;28:339–50.
PubMed
Article
Google Scholar
Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140:124–31.
PubMed
Article
Google Scholar
Nestel PJ, Havel RJ, Bezman A. Sites of initial removal of chylomicron triglyceride fatty acids from the blood. J Clin Invest. 1962;41:1915–21.
PubMed
Article
CAS
Google Scholar
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;115:1343–51.
PubMed
CAS
Google Scholar
Bradbury MW. Lipid metabolism and liver inflammation. I. Hepatic fatty acid uptake: possible role in steatosis. Am J Physiol Gastrointest Liver Physiol. 2006;290:G194–8.
PubMed
Article
CAS
Google Scholar
Doege H, Stahl A. Protein-mediated fatty acid uptake: novel insights from in vivo models. Physiology (Bethesda). 2006;21:259–68.
Article
CAS
Google Scholar
Hirsch D, Stahl A, Lodish HF. A family of fatty acid transporters conserved from mycobacterium to man. Proc Natl Acad Sci USA. 1998;95:8625–9.
PubMed
Article
CAS
Google Scholar
Doege H, Baillie RA, Ortegon AM, Tsang B, Wu Q, Punreddy S, et al. Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis. Gastroenterology. 2006;130:1245–58.
PubMed
Article
CAS
Google Scholar
Falcon A, Doege H, Fluitt A, Tsang B, Watson N, Kay MA, et al. FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase. Am J Physiol Endocrinol Metab. 2010;299:E384–93.
PubMed
Article
CAS
Google Scholar
Su X, Abumrad NA. Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab. 2009;20:72–7.
PubMed
Article
CAS
Google Scholar
Hajri T, Han XX, Bonen A, Abumrad NA. Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice. J Clin Invest. 2002;109:1381–9.
PubMed
CAS
Google Scholar
Hall AM, Smith AJ, Bernlohr DA. Characterization of the Acyl-CoA synthetase activity of purified murine fatty acid transport protein 1. J Biol Chem. 2003;278:43008–13.
PubMed
Article
CAS
Google Scholar
Richards MR, Harp JD, Ory DS, Schaffer JE. Fatty acid transport protein 1 and long-chain acyl coenzyme A synthetase 1 interact in adipocytes. J Lipid Res. 2006;47:665–72.
PubMed
Article
CAS
Google Scholar
Li LO, Klett EL, Coleman RA. Acyl-CoA synthesis, lipid metabolism and lipotoxicity. Biochim Biophys Acta. 2010;1801:246–51.
PubMed
Article
CAS
Google Scholar
Soupene E, Kuypers FA. Mammalian long-chain acyl-CoA synthetases. Exp Biol Med (Maywood). 2008;233:507–21.
Article
CAS
Google Scholar
Li LO, Ellis JM, Paich HA, Wang S, Gong N, Altshuller G, et al. Liver-specific loss of long chain acyl-CoA synthetase-1 decreases triacylglycerol synthesis and beta-oxidation and alters phospholipid fatty acid composition. J Biol Chem. 2009;284:27816–26.
PubMed
Article
CAS
Google Scholar
Bu SY, Mashek DG. Hepatic long-chain acyl-CoA synthetase 5 mediates fatty acid channeling between anabolic and catabolic pathways. J Lipid Res. 2010;51:3270–80.
PubMed
Article
Google Scholar
Mashek DG, McKenzie MA, Van Horn CG, Coleman RA. Rat long chain acyl-CoA synthetase 5 increases fatty acid uptake and partitioning to cellular triacylglycerol in McArdle-RH7777 cells. J Biol Chem. 2006;281:945–50.
PubMed
Article
CAS
Google Scholar
Milger K, Herrmann T, Becker C, Gotthardt D, Zickwolf J, Ehehalt R, et al. Cellular uptake of fatty acids driven by the ER-localized acyl-CoA synthetase FATP4. J Cell Sci. 2006;119:4678–88.
PubMed
Article
CAS
Google Scholar
Holt HB, Wild SH, Wood PJ, Zhang J, Darekar AA, Dewbury K, et al. Non-esterified fatty acid concentrations are independently associated with hepatic steatosis in obese subjects. Diabetologia. 2006;49:141–8.
PubMed
Article
CAS
Google Scholar
Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology. 2008;134:424–31.
PubMed
Article
CAS
Google Scholar
Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2010;51:679–89.
PubMed
Article
CAS
Google Scholar
Hwang JH, Stein DT, Barzilai N, Cui MH, Tonelli J, Kishore P, et al. Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies. Am J Physiol Endocrinol Metab. 2007;293:E1663–9.
PubMed
Article
CAS
Google Scholar
Greco D, Kotronen A, Westerbacka J, Puig O, Arkkila P, Kiviluoto T, et al. Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol. 2008;294:G1281–7.
PubMed
Article
CAS
Google Scholar
Miquilena-Colina ME, Lima-Cabello E, Sanchez-Campos S, Garcia-Mediavilla MV, Fernandez-Bermejo M, Lozano-Rodriguez T, et al. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut. 2011;60:1394–402.
PubMed
Article
CAS
Google Scholar
Koonen DP, Jacobs RL, Febbraio M, Young ME, Soltys CL, Ong H, et al. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes. 2007;56:2863–71.
PubMed
Article
CAS
Google Scholar
Doege H, Grimm D, Falcon A, Tsang B, Storm TA, Xu H, et al. Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia. J Biol Chem. 2008;283:22186–92.
PubMed
Article
CAS
Google Scholar
Nie B, Park HM, Kazantzis M, Lin M, Henkin A, Ng S, et al. Specific bile acids inhibit hepatic fatty acid uptake in mice. Hepatology. 2012;56:1300–10.
PubMed
Article
CAS
Google Scholar
Csaki LS, Reue K. Lipins: multifunctional lipid metabolism proteins. Annu Rev Nutr. 2010;30:257–72.
PubMed
Article
CAS
Google Scholar
Ferre 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.
PubMed
Article
CAS
Google Scholar
Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109:1125–31.
PubMed
CAS
Google Scholar
Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science. 2001;294:1866–70.
PubMed
Article
CAS
Google Scholar
Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, et al. Role of LXRs in control of lipogenesis. Genes Dev. 2000;14:2831–8.
PubMed
Article
CAS
Google Scholar
Uyeda K, Repa JJ. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. 2006;4:107–10.
PubMed
Article
CAS
Google Scholar
Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148:852–71.
PubMed
Article
CAS
Google Scholar
Li S, Brown MS, Goldstein JL. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci USA. 2010;107:3441–6.
PubMed
Article
CAS
Google Scholar
Yecies JL, Zhang HH, Menon S, Liu S, Yecies D, Lipovsky AI, et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab. 2011;14:21–32.
PubMed
Article
CAS
Google Scholar
Eaton S, Bartlett K, Pourfarzam M. Mammalian mitochondrial beta-oxidation. Biochem J. 1996;320:345–57.
PubMed
CAS
Google Scholar
McGarry JD, Foster DW. Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem. 1980;49:395–420.
PubMed
Article
CAS
Google Scholar
Sidossis LS, Stuart CA, Shulman GI, Lopaschuk GD, Wolfe RR. Glucose plus insulin regulate fat oxidation by controlling the rate of fatty acid entry into the mitochondria. J Clin Invest. 1996;98:2244–50.
PubMed
Article
CAS
Google Scholar
Mao J, DeMayo FJ, Li H, Abu-Elheiga L, Gu Z, Shaikenov TE, et al. Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc Natl Acad Sci USA. 2006;103:8552–7.
PubMed
Article
CAS
Google Scholar
Savage DB, Choi CS, Samuel VT, Liu ZX, Zhang D, Wang A, et al. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest. 2006;116:817–24.
PubMed
Article
CAS
Google Scholar
Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil SJ. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science. 2001;291:2613–6.
PubMed
Article
CAS
Google Scholar
Foster DW. Malonyl-CoA: the regulator of fatty acid synthesis and oxidation. J Clin Invest. 2012;122:1958–9.
PubMed
Article
CAS
Google Scholar
Longuet C, Sinclair EM, Maida A, Baggio LL, Maziarz M, Charron MJ, et al. The glucagon receptor is required for the adaptive metabolic response to fasting. Cell Metab. 2008;8:359–71.
PubMed
Article
CAS
Google Scholar
Mandard S, Muller M, Kersten S. Peroxisome proliferator-activated receptor alpha target genes. Cell Mol Life Sci. 2004;61:393–416.
PubMed
Article
CAS
Google Scholar
Kliewer SA, Mangelsdorf DJ. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr. 2010;91:254S–7S.
PubMed
Article
CAS
Google Scholar
Canto C, Auwerx J. Cell biology. FGF21 takes a fat bite. Science. 2012;336:675–6.
PubMed
Article
CAS
Google Scholar
Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol. 2012;13:225–38.
PubMed
CAS
Google Scholar
Schmid AI, Szendroedi J, Chmelik M, Krssak M, Moser E, Roden M. Liver ATP synthesis is lower and relates to insulin sensitivity in patients with type 2 diabetes. Diabetes Care. 2011;34:448–53.
PubMed
Article
CAS
Google Scholar
Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA. 1999;282:1659–64.
PubMed
Article
CAS
Google Scholar
Satapati S, Sunny NE, Kucejova B, Fu X, He TT, Mendez-Lucas A, et al. Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. J Lipid Res. 2012;53:1080–92.
PubMed
Article
CAS
Google Scholar
Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183–92.
PubMed
Article
CAS
Google Scholar
Pessayre D, Fromenty B. NASH: a mitochondrial disease. J Hepatol. 2005;42:928–40.
PubMed
Article
CAS
Google Scholar
Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res. 2003;44:22–32.
PubMed
Article
CAS
Google Scholar
Tiwari S, Siddiqi SA. Intracellular trafficking and secretion of VLDL. Arterioscler Thromb Vasc Biol. 2012;32:1079–86.
PubMed
Article
CAS
Google Scholar
Gibbons GF. Assembly and secretion of hepatic very-low-density lipoprotein. Biochem J. 1990;268:1–13.
PubMed
CAS
Google Scholar
Ginsberg HN, Fisher EA. The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism. J Lipid Res. 2009;50(Suppl):S162–6.
PubMed
Article
Google Scholar
Kamagate A, Dong HH. FoxO1 integrates insulin signaling to VLDL production. Cell Cycle. 2008;7:3162–70.
PubMed
Article
CAS
Google Scholar
Tanoli T, Yue P, Yablonskiy D, Schonfeld G. Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity. J Lipid Res. 2004;45:941–7.
PubMed
Article
CAS
Google Scholar
Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR. The role of the microsomal triglyceride transfer protein in abetalipoproteinemia. Annu Rev Nutr. 2000;20:663–97.
PubMed
Article
CAS
Google Scholar
Raabe M, Veniant MM, Sullivan MA, Zlot CH, Bjorkegren J, Nielsen LB, et al. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice. J Clin Invest. 1999;103:1287–98.
PubMed
Article
CAS
Google Scholar
Tietge UJ, Bakillah A, Maugeais C, Tsukamoto K, Hussain M, Rader DJ. Hepatic overexpression of microsomal triglyceride transfer protein (MTP) results in increased in vivo secretion of VLDL triglycerides and apolipoprotein B. J Lipid Res. 1999;40:2134–9.
PubMed
CAS
Google Scholar
Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007;356:148–56.
PubMed
Article
CAS
Google Scholar
Choi SH, Ginsberg HN. Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends Endocrinol Metab. 2011;22:353–63.
PubMed
Article
Google Scholar
Ota T, Gayet C, Ginsberg HN. Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents. J Clin Invest. 2008;118:316–32.
PubMed
Article
CAS
Google Scholar
Li JZ, Huang Y, Karaman R, Ivanova PT, Brown HA, Roddy T, et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest. 2012;122:4130–44.
PubMed
Article
CAS
Google Scholar