Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of metabolic abnormalities ranging from simple hepatic steatosis (accumulation of neutral lipid) to development of steatotic lesions, steatohepatitis, and cirrhosis. NAFLD is extremely prevalent in obese individuals and with the epidemic of obesity; nonalcoholic steatohepatitis (NASH) has become the most common cause of liver disease in the developed world. NASH is rapidly emerging as a prominent cause of liver failure and transplantation. Moreover, hepatic steatosis is tightly linked to risk of developing insulin resistance, diabetes, and cardiovascular disease. Abnormalities in hepatic lipid metabolism are part and parcel of the development of NAFLD and human genetic studies and work conducted in experimentally tractable systems have identified a number of enzymes involved in fat synthesis and degradation that are linked to NAFLD susceptibility as well as progression to NASH. The goal of this review is to summarize the current state of our knowledge on these pathways and focus on how they contribute to etiology of NAFLD and related metabolic diseases. 1. Introduction Overwhelming evidence links obesity with increased risk for several chronic diseases including insulin resistance, diabetes mellitus, dyslipidemias, and nonalcoholic fatty liver disease (NAFLD). The condition, NAFLD, encompasses both hepatic steatosis (the accumulation of neutral lipid within the cytosol of hepatocytes) and the more severe nonalcoholic steatohepatitis (NASH; hepatic inflammation and fibrosis associated with steatotic lesions). With the epidemic of obesity in the USA, the occurrence of NAFLD has risen exuberantly, becoming the most common cause of liver disease [1, 2]. It is now estimated that 14–24% of the general population and up to 80% of morbidly obese subjects have contracted NAFLD [3–6]. Although hepatic steatosis is extremely prevalent, only a subset of afflicted individuals experience severe liver damage and progress to cirrhosis. Hepatic steatosis promotes an inflammatory state including augmented production of reactive oxygen species (ROS) and proinflammatory cytokines. This “second hit” is believed to be required to drive the transition from simple steatosis to steatohepatitis [5, 7–9]. Although the exact cause of the inflammation is difficult to pinpoint, hepatic steatosis is linked to heightened production of ROS [7, 10–13], which are known to cause mitochondrial damage. Mitochondrial injury further exacerbates ROS production, diminishes the capacity to oxidize excess fatty acids, and is also
References
[1]
J. M. Clark and A. M. Diehl, “Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis,” Journal of the American Medical Association, vol. 289, no. 22, pp. 3000–3004, 2003.
[2]
J. M. Clark, F. L. Brancati, and A. M. Diehl, “Nonalcoholic fatty liver disease,” Gastroenterology, vol. 122, no. 6, pp. 1649–1657, 2002.
[3]
W. Youssef and A. J. McCullough, “Diabetes mellitus, obesity, and hepatic steatosis,” Seminars in Gastrointestinal Disease, vol. 13, no. 1, pp. 17–30, 2002.
[4]
W. I. Youssef and A. J. McCullough, “Steatohepatitis in obese individuals,” Bailliere's Best Practice and Research in Clinical Gastroenterology, vol. 16, no. 5, pp. 733–747, 2002.
[5]
J. D. Browning and J. D. Horton, “Molecular mediators of hepatic steatosis and liver injury,” Journal of Clinical Investigation, vol. 114, no. 2, pp. 147–152, 2004.
[6]
J. D. Browning, L. S. Szczepaniak, R. Dobbins et al., “Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity,” Hepatology, vol. 40, no. 6, pp. 1387–1395, 2004.
[7]
K. Begriche, A. Igoudjil, D. Pessayre, and B. Fromenty, “Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it,” Mitochondrion, vol. 6, no. 1, pp. 1–38, 2006.
[8]
I. R. Wanless and K. Shiota, “The pathogenesis of nonalcoholic steatohepatitis and other fatty liver diseases: a four-step model including the role of lipid release and hepatic venular obstruction in the progression to cirrhosis,” Seminars in Liver Disease, vol. 24, no. 1, pp. 99–106, 2004.
[9]
K. Te Sligte, I. Bourass, J. P. Sels, A. Driessen, R. W. Stockbrugger, and G. H. Koek, “Non-alcoholic steatohepatitis: review of a growing medical problem,” European Journal of Internal Medicine, vol. 15, no. 1, pp. 10–21, 2004.
[10]
C. Garcia-Ruiz, A. Colell, A. Morales, N. Kaplowitz, and J. C. Fernandez-Checa, “Role of oxidative stress generated from the mitochondrial electron transport chain and mitochondrial glutathione status in loss of mitochondrial function and activation of transcription factor nuclear factor-κB: studies with isolated mitochondria and rat hepatocytes,” Molecular Pharmacology, vol. 48, no. 5, pp. 825–834, 1995.
[11]
B. Fromenty, M. A. Robin, A. Igoudjil, A. Mansouri, and D. Pessayre, “The ins and outs of mitochondrial dysfunction in NASH,” Diabetes and Metabolism, vol. 30, no. 2, pp. 121–138, 2004.
[12]
A. J. Sanyal, C. Campbell-Sargent, F. Mirshahi et al., “Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities,” Gastroenterology, vol. 120, no. 5, pp. 1183–1192, 2001.
[13]
S. H. Caldwell, R. H. Swerdlow, E. M. Khan et al., “Mitochondrial abnormalities in non-alcoholic steatohepatitis,” Journal of Hepatology, vol. 31, no. 3, pp. 430–434, 1999.
[14]
S. Klein, B. Mittendorfer, J. C. Eagon et al., “Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease,” Gastroenterology, vol. 130, no. 6, pp. 1564–1572, 2006.
[15]
S. W. Coppack, D. L. Chinkes, J. M. Miles, B. W. Patterson, and S. Klein, “A multicompartmental model of in vivo adipose tissue glycerol kinetics and capillary permeability in lean and obese humans,” Diabetes, vol. 54, no. 7, pp. 1934–1941, 2005.
[16]
S. W. Coppack, J. F. Horowitz, D. S. Paramore, P. E. Cryer, H. D. Royal, and S. Klein, “Whole body, adipose tissue, and forearm norepinephrine kinetics in lean and obese women,” American Journal of Physiology—Endocrinology and Metabolism, vol. 275, no. 5, pp. E830–E834, 1998.
[17]
R. R. Townsend and S. Klein, “Lipolytic sensitivity and response to fasting in normotensive and hypertensive obese humans,” Metabolism: Clinical and Experimental, vol. 46, no. 9, pp. 1080–1084, 1997.
[18]
B. Mittendorfer, B. W. Patterson, S. Klein, and L. S. Sidossis, “VLDL-triglyceride kinetics during hyperglycemia-hyperinsulinemia: effects of sex and obesity,” American Journal of Physiology—Endocrinology and Metabolism, vol. 284, no. 4, pp. E708–E715, 2003.
[19]
B. Mittendorfer, B. W. Patterson, and S. Klein, “Effect of weight loss on VLDL-triglyceride and apoB-100 kinetics in women with abdominal obesity,” American Journal of Physiology—Endocrinology and Metabolism, vol. 284, no. 3, pp. E549–E556, 2003.
[20]
I. Shimomura, M. Matsuda, R. E. Hammer, Y. Bashmakov, M. S. Brown, and J. L. Goldstein, “Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice,” Molecular Cell, vol. 6, no. 1, pp. 77–86, 2000.
[21]
Y. Shi and D. Cheng, “Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism,” American Journal of Physiology—Endocrinology and Metabolism, vol. 297, no. 1, pp. E10–E18, 2009.
[22]
J. Cao, E. Hawkins, J. Brozinick et al., “A predominant role of Acyl-CoA:monoacylglycerol acyltransferase-2 in dietary fat absorption implicated by tissue distribution, subcellular localization, and up-regulation by high fat diet,” Journal of Biological Chemistry, vol. 279, no. 18, pp. 18878–18886, 2004.
[23]
F. Wilfling, H. Wang, J. T. Haas, et al., “Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets,” Developmental Cell, vol. 24, no. 4, pp. 384–399, 2013.
[24]
B. R. Bacon, M. J. Farahvash, C. G. Janney, and B. A. Neuschwander-Tetri, “Nonalcoholic steatohepatitis: an expanded clinical entity,” Gastroenterology, vol. 107, no. 4, pp. 1103–1109, 1994.
[25]
M. J. Contos, J. Choudhury, A. S. Mills, and A. J. Sanyal, “The histologic spectrum of nonalcoholic fatty liver disease,” Clinics in Liver Disease, vol. 8, no. 3, pp. 481–500, 2004.
[26]
B. Fromenty, A. Berson, and D. Pessayre, “Microvesicular steatosis and steatohepatitis: role of mitochondrial dysfunction and lipid peroxidation,” Journal of Hepatology, Supplement, vol. 26, no. 1, pp. 13–22, 1997.
[27]
E. Freneaux, G. Labbe, P. Letteron et al., “Inhibition of the mitochondrial oxidation of fatty acids by tetracycline in mice and in man: possible role in microvesicular steatosis induced by this antibiotic,” Hepatology, vol. 8, no. 5, pp. 1056–1062, 1988.
[28]
A. D. Burt, A. Mutton, and C. P. Day, “Diagnosis and interpretation of steatosis and steatohepatitis,” Seminars in Diagnostic Pathology, vol. 15, no. 4, pp. 246–258, 1998.
[29]
A. M. Hall, E. M. Brunt, Z. Chen et al., “Dynamic and differential regulation of proteins that coat lipid droplets in fatty liver dystrophic mice,” Journal of Lipid Research, vol. 51, no. 3, pp. 554–563, 2010.
[30]
C. Zhang, A. A. Wendel, M. R. Keogh, T. E. Harris, J. Chen, and R. A. Coleman, “Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 5, pp. 1667–1672, 2012.
[31]
O. Bezy, T. T. Tran, J. Pihlajam？ki et al., “PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans,” Journal of Clinical Investigation, vol. 121, no. 6, pp. 2504–2517, 2011.
[32]
V. T. Samuel, Z.-X. Liu, A. Wang et al., “Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease,” Journal of Clinical Investigation, vol. 117, no. 3, pp. 739–745, 2007.
[33]
G.-S. Han, W.-I. Wu, and G. M. Carman, “The Saccharomyces cerevisiae lipin homolog is a Mg2+-dependent phosphatidate phosphatase enzyme,” Journal of Biological Chemistry, vol. 281, no. 14, pp. 9210–9218, 2006.
[34]
A. A. Wendel, T. M. Lewin, and R. A. Coleman, “Glycerol-3-phosphate acyltransferases: rate limiting enzymes of triacylglycerol biosynthesis,” Biochimica et Biophysica Acta—Molecular and Cell Biology of Lipids, vol. 1791, no. 6, pp. 501–506, 2009.
[35]
A. A. Wendel, D. E. Cooper, O. R. Ilkayeva, D. M. Muoio, and R. A. Coleman, “Glycerol-3-phosphate acyltransferase (GPAT)-1, but not GPAT4, incorporates newly synthesized fatty acids into triacylglycerol and diminishes fatty acid oxidation,” The Journal of Biological Chemistry, vol. 288, no. 38, pp. 27299–27306, 2013.
[36]
C. A. Nagle, J. An, M. Shiota et al., “Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance,” Journal of Biological Chemistry, vol. 282, no. 20, pp. 14807–14815, 2007.
[37]
S. Neschen, K. Morino, L. E. Hammond et al., “Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockout mice,” Cell Metabolism, vol. 2, no. 1, pp. 55–65, 2005.
[38]
L. E. Hammond, P. A. Gallagher, S. Wang et al., “Mitochondrial glycerol-3-phosphate acyltransferase-deficient mice have reduced weight and liver triacylglycerol content and altered glycerolipid fatty acid composition,” Molecular and Cellular Biology, vol. 22, no. 23, pp. 8204–8214, 2002.
[39]
M. Yazdi, A. Ahnmark, L. William-Olsson et al., “The role of mitochondrial glycerol-3-phosphate acyltransferase-1 in regulating lipid and glucose homeostasis in high-fat diet fed mice,” Biochemical and Biophysical Research Communications, vol. 369, no. 4, pp. 1065–1070, 2008.
[40]
A. A. Wendel, L. O. Li, Y. Li, G. W. Cline, G. I. Shulman, and R. A. Coleman, “Glycerol-3-phosphate acyltransferase 1 deficiency in ob/ob mice diminishes hepatic steatosis but does not protect against insulin resistance or obesity,” Diabetes, vol. 59, no. 6, pp. 1321–1329, 2010.
[41]
H. Xu, D. Wilcox, P. Nguyen et al., “Hepatic knockdown of mitochondrial GPAT1 in ob/ob mice improves metabolic profile,” Biochemical and Biophysical Research Communications, vol. 349, no. 1, pp. 439–448, 2006.
[42]
R. E. Gimeno and J. Cao, “Mammalian glycerol-3-phosphate acyltransferases: new genes for an old activity,” Journal of Lipid Research, vol. 49, no. 10, pp. 2079–2088, 2008.
[43]
C. A. Nagle, L. Vergnes, H. Dejong et al., “Identification of a novel sn-glycerol-3-phosphate acyltransferase isoform, GPAT4, as the enzyme deficient in Agpat6-/- mice,” Journal of Lipid Research, vol. 49, no. 4, pp. 823–831, 2008.
[44]
L. Vergnes, A. P. Beigneux, R. Davis, S. M. Watkins, S. G. Young, and K. Reue, “Agpat6 deficiency causes subdermal lipodystrophy and resistance to obesity,” Journal of Lipid Research, vol. 47, no. 4, pp. 745–754, 2006.
[45]
M. Kumari, G. Schoiswohl, C. Chitraju et al., “Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase,” Cell Metabolism, vol. 15, no. 5, pp. 691–702, 2012.
[46]
D. W. Leung, “The structure and functions of human lysophosphatidic acid acyltransferases,” Front Biosci, vol. 6, pp. D944–D953, 2001.
[47]
V. A. Cortés, D. E. Curtis, S. Sukumaran et al., “Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy,” Cell Metabolism, vol. 9, no. 2, pp. 165–176, 2009.
[48]
A. K. Agarwal, E. Arioglu, S. De Almeida et al., “AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34,” Nature Genetics, vol. 31, no. 1, pp. 21–23, 2002.
[49]
J. Donkor, M. Sariahmetoglu, J. Dewald, D. N. Brindley, and K. Reue, “Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns,” Journal of Biological Chemistry, vol. 282, no. 6, pp. 3450–3457, 2007.
[50]
H. Ren, L. Federico, H. Huang et al., “A phosphatidic acid binding/nuclear localization motif determines lipin1 function in lipid metabolism and adipogenesis,” Molecular Biology of the Cell, vol. 21, no. 18, pp. 3171–3181, 2010.
[51]
B. N. Finck, M. C. Gropler, Z. Chen et al., “Lipin 1 is an inducible amplifier of the hepatic PGC-1α/PPARα regulatory pathway,” Cell Metabolism, vol. 4, no. 3, pp. 199–210, 2006.
[52]
T. E. Harris, T. A. Huffman, A. Chi et al., “Insulin controls subcellular localization and multisite phosphorylation of the phosphatidic acid phosphatase, lipin 1,” Journal of Biological Chemistry, vol. 282, no. 1, pp. 277–286, 2007.
[53]
M. C. Gropler, T. E. Harris, A. M. Hall et al., “Lipin 2 is a liver-enriched phosphatidate phosphohydrolase enzyme that is dynamically regulated by fasting andobesity in mice,” Journal of Biological Chemistry, vol. 284, no. 11, pp. 6763–6772, 2009.
[54]
M. Hu, F. Wang, X. Li et al., “Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice,” Hepatology, vol. 55, no. 2, pp. 437–446, 2012.
[55]
M. Hu, H. Yin, M. S. Mitra, et al., “Hepatic-specific lipin-1 deficiency exacerbates experimental alcohol-induced steatohepatitis in mice,” Hepatology, vol. 58, no. 6, pp. 1953–1963, 2013.
[56]
Z. Chen, M. C. Gropler, J. Norris, J. C. Lawrence Jr., T. E. Harris, and B. N. Finck, “Alterations in hepatic metabolism in fld mice reveal a role for lipin 1 in regulating VLDL-triacylglyceride secretion,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 10, pp. 1738–1744, 2008.
[57]
A. Zeharia, A. Shaag, R. H. Houtkooper et al., “Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood,” American Journal of Human Genetics, vol. 83, no. 4, pp. 489–494, 2008.
[58]
C. Michot, L. Hubert, M. Brivet et al., “LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood,” Human Mutation, vol. 31, no. 7, pp. E1564–E1573, 2010.
[59]
C. Michot, L. Hubert, N. B. Romero et al., “Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia,” Journal of Inherited Metabolic Disease, vol. 35, no. 6, pp. 1119–1128, 2012.
[60]
V. Nobili, B. Donati, N. Panera, et al., “A Four-polymorphisms risk score predicts steatohepatitis in children with non-alcoholic fatty liver disease,” Journal of Pediatric Gastroenterology and Nutrition. In press.
[61]
L. Valenti, B. M. Motta, A. Alisi et al., “LPIN1 rs13412852 polymorphism in pediatric nonalcoholic fatty liver disease,” Journal of Pediatric Gastroenterology and Nutrition, vol. 54, no. 5, pp. 588–593, 2012.
[62]
D. Ryu, K.-J. Oh, H.-Y. Jo et al., “TORC2 regulates hepatic insulin signaling via a mammalian phosphatidic acid phosphatase, LIPIN1,” Cell Metabolism, vol. 9, no. 3, pp. 240–251, 2009.
[63]
M. A. Croce, J. C. Eagon, L. L. LaRiviere, K. M. Korenblat, S. Klein, and B. N. Finck, “Hepatic lipin 1β expression is diminished in insulin-resistant obese subjects and is reactivated by marked weight loss,” Diabetes, vol. 56, no. 9, pp. 2395–2399, 2007.
[64]
J. Donkor, P. Zhang, S. Wong et al., “A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2,” Journal of Biological Chemistry, vol. 284, no. 43, pp. 29968–29978, 2009.
[65]
J. R. Dwyer, J. Donkor, P. Zhang, et al., “Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 37, pp. E2486–E2495, 2012.
[66]
D. Ryu, W.-Y. Seo, Y.-S. Yoon et al., “Endoplasmic reticulum stress promotes LIPIN2-dependent hepatic insulin resistance,” Diabetes, vol. 60, no. 4, pp. 1072–1081, 2011.
[67]
Y. G. Yue, Y. Q. Chen, Y. Zhang et al., “The acyl coenzymeA:monoacylglycerol acyltransferase 3 (MGAT3) gene is a pseudogene in mice but encodes a functional enzyme in rats,” Lipids, vol. 46, no. 6, pp. 513–520, 2011.
[68]
A. M. Hall, K. Kou, Z. Chen et al., “Evidence for regulated monoacylglycerol acyltransferase expression and activity in human liver,” Journal of Lipid Research, vol. 53, no. 5, pp. 990–999, 2012.
[69]
C.-L. E. Yen, S. J. Stone, S. Cases, P. Zhou, and R. V. Farese Jr., “Identification of a gene encoding MGAT1, a monoacylglycerol acyltransferase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 13, pp. 8512–8517, 2002.
[70]
C.-L. E. Yen and R. V. Farese Jr., “MGAT2, a monoacylglycerol acyltransferase expressed in the small intestine,” Journal of Biological Chemistry, vol. 278, no. 20, pp. 18532–18537, 2003.
[71]
Y. J. Lee, E. H. Ko, J. E. Kim, et al., “Nuclear receptor PPARgamma-regulated monoacylglycerol O-acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 34, pp. 13656–13661, 2012.
[72]
A. M. Hall, N. Soufi, K. T. Chambers, et al., “Abrogating monoacylglycerol acyltransferase activity in liver improves glucose tolerance and hepatic insulin signaling in obese mice,” Diabetes, 2014.
[73]
C.-L. E. Yen, M.-L. Cheong, C. Grueter et al., “Deficiency of the intestinal enzyme acyl CoA:monoacylglycerol acyltransferase-2 protects mice from metabolic disorders induced by high-fat feeding,” Nature Medicine, vol. 15, no. 4, pp. 442–446, 2009.
[74]
Y. Gao, D. W. Nelson, T. Banh, M. I. Yen, and C. L. Yen, “Intestine-specific expression of MOGAT2 partially restores metabolic efficiency in Mogat2-deficient mice,” The Journal of Lipid Research, vol. 54, no. 6, pp. 1644–1652, 2013.
[75]
S. J. Smith, S. Cases, D. R. Jensen et al., “Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat,” Nature Genetics, vol. 25, no. 1, pp. 87–90, 2000.
[76]
C. J. Villanueva, M. Monetti, M. Shih et al., “Specific role for acyl CoA:diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids,” Hepatology, vol. 50, no. 2, pp. 434–442, 2009.
[77]
H. C. Chen, S. J. Smith, Z. Ladha et al., “Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1,” Journal of Clinical Investigation, vol. 109, no. 8, pp. 1049–1055, 2002.
[78]
S. C. Cheol, D. B. Savage, A. Kulkarni et al., “Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance,” Journal of Biological Chemistry, vol. 282, no. 31, pp. 22678–22688, 2007.
[79]
K. Yamaguchi, L. Yang, S. McCall et al., “Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis,” Hepatology, vol. 47, no. 2, pp. 625–635, 2008.
[80]
E. Herker, C. Harris, C. Hernandez et al., “Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1,” Nature Medicine, vol. 16, no. 11, pp. 1295–1298, 2010.
[81]
C. Harris, E. Herker, R. V. Farese Jr., and M. Ott, “Hepatitis C virus core protein decreases lipid droplet turnover: a mechanism for core-induced steatosis,” Journal of Biological Chemistry, vol. 286, no. 49, pp. 42615–42625, 2011.
[82]
S. J. Stone, H. M. Myers, S. M. Watkins et al., “Lipopenia and skin barrier abnormalities in DGAT2-deficient mice,” Journal of Biological Chemistry, vol. 279, no. 12, pp. 11767–11776, 2004.
[83]
X. X. Yu, S. F. Murray, S. K. Pandey et al., “Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice,” Hepatology, vol. 42, no. 2, pp. 362–371, 2005.
[84]
K. Yamaguchi, L. Yang, S. McCall et al., “Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis,” Hepatology, vol. 45, no. 6, pp. 1366–1374, 2007.
[85]
M. Monetti, M. C. Levin, M. J. Watt et al., “Dissociation of hepatic steatosis and insulin resistance in mice overexpressing dgat in the liver,” Cell Metabolism, vol. 6, no. 1, pp. 69–78, 2007.
[86]
F. R. Jornayvaz, A. L. Birkenfeld, M. J. Jurczak et al., “Hepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 14, pp. 5748–5752, 2011.
[87]
A. R. Kimmel, D. L. Brasaemle, M. McAndrews-Hill, C. Sztalryd, and C. Londos, “Adoption of PERILIPIN as a unifying nomenclature for the mammalian PAT-family of intracellular lipid storage droplet proteins,” Journal of Lipid Research, vol. 51, no. 3, pp. 468–471, 2010.
[88]
A. S. Greenberg, J. J. Egan, S. A. Wek, N. B. Garty, E. J. Blanchette-Mackie, and C. Londos, “Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets,” Journal of Biological Chemistry, vol. 266, no. 17, pp. 11341–11346, 1991.
[89]
H. Fujii, Y. Ikura, J. Arimoto et al., “Expression of perilipin and adipophilin in nonalcoholic fatty liver disease; relevance to oxidative injury and hepatocyte ballooning,” Journal of Atherosclerosis and Thrombosis, vol. 16, no. 6, pp. 893–901, 2009.
[90]
L. M. Pawella, M. Hashani, E. Eiteneuer, et al., “Perilipin discerns chronic from acute hepatocellular steatosis,” Journal of Hepatology, vol. 60, no. 3, pp. 633–642, 2013.
[91]
H. W. Heid, R. Moll, I. Schwetlick, H.-R. Rackwitz, and T. W. Keenan, “Adipophilin is a specific marker of lipid accumulation in diverse cell types and diseases,” Cell and Tissue Research, vol. 294, no. 2, pp. 309–321, 1998.
[92]
W. Motomura, M. Inoue, T. Ohtake et al., “Up-regulation of ADRP in fatty liver in human and liver steatosis in mice fed with high fat diet,” Biochemical and Biophysical Research Communications, vol. 340, no. 4, pp. 1111–1118, 2006.
[93]
B. H.-J. Chang, L. Li, A. Paul et al., “Protection against fatty liver but normal adipogenesis in mice lacking adipose differentiation-related protein,” Molecular and Cellular Biology, vol. 26, no. 3, pp. 1063–1076, 2006.
[94]
J. L. McManaman, E. S. Bales, D. J. Orlicky, et al., “Perilipin-2-null mice are protected against diet-induced obesity, adipose inflammation, and fatty liver disease,” The Journal of Lipid Research, vol. 54, no. 5, pp. 1346–1359, 2013.
[95]
B. H.-J. Chang, L. Li, P. Saha, and L. Chan, “Absence of adipose differentiation related protein upregulates hepatic VLDL secretion, relieves hepatosteatosis, and improves whole body insulin resistance in leptin-deficient mice,” Journal of Lipid Research, vol. 51, no. 8, pp. 2132–2142, 2010.
[96]
Y. Imai, S. Boyle, G. M. Varela, et al., “Effects of perilipin 2 antisense oligonucleotide treatment on hepatic lipid metabolism and gene expression,” Physiological Genomics, vol. 44, no. 22, pp. 1125–1131, 2012.
[97]
G. M. Varela, D. A. Antwi, R. Dhir et al., “Inhibition of ADRP prevents diet-induced insulin resistance,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 295, no. 3, pp. G621–G628, 2008.
[98]
H. Li, Y. Song, L. J. Zhang, et al., “LSDP5 enhances triglyceride storage in hepatocytes by influencing lipolysis and fatty acid beta-oxidation of lipid droplets,” PLoS ONE, vol. 7, no. 6, Article ID e36712, 2012.
[99]
V. Puri, S. Ranjit, S. Konda et al., “Cidea is associated with lipid droplets and insulin sensitivity in humans,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 22, pp. 7833–7838, 2008.
[100]
L. Zhou, L. Xu, J. Ye, et al., “Cidea promotes hepatic steatosis by sensing dietary fatty acids,” Hepatology, vol. 56, no. 1, pp. 95–107, 2012.
[101]
Y. Jinno, M. Nakakuki, A. Sato et al., “Cide-a and Cide-c are induced in the progression of hepatic steatosis and inhibited by eicosapentaenoic acid,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 83, no. 2, pp. 75–81, 2010.
[102]
A. M. Hall, E. M. Brunt, S. Klein, and B. N. Finck, “Hepatic expression of cell death-inducing DFFA-like effector C in obese subjects is reduced by marked weight loss,” Obesity, vol. 18, no. 2, pp. 417–419, 2010.
[103]
Z. Zhou, S. Y. Toh, Z. Chen et al., “Cidea-deficient mice have lean phenotype and are resistant to obesity,” Nature Genetics, vol. 35, no. 1, pp. 49–56, 2003.
[104]
J. Z. Li, J. Ye, B. Xue et al., “Cideb regulates diet-induced obesity, liver steatosis, and insulin sensitivity by controlling lipogenesis and fatty acid oxidation,” Diabetes, vol. 56, no. 10, pp. 2523–2532, 2007.
[105]
J. Ye, J. Z. Li, Y. Liu et al., “Cideb, an ER- and lipid droplet-associated protein, mediates vldl lipidation and maturation by interacting with apolipoprotein B,” Cell Metabolism, vol. 9, no. 2, pp. 177–190, 2009.
[106]
Z. Chen, J. Y. Norris, and B. N. Finck, “Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) stimulates VLDL assembly through activation of cell death-inducing DFFA-like effector B (CideB),” Journal of Biological Chemistry, vol. 285, no. 34, pp. 25996–26004, 2010.
[107]
S. Tiwari, S. Siddiqi, and S. A. Siddiqi, “CideB protein is required for the biogenesis of very low density lipoprotein (VLDL) transport vesicle,” The Journal of Biological Chemistry, vol. 288, no. 7, pp. 5157–5165, 2013.
[108]
X. Li, J. Ye, L. Zhou, et al., “Opposing roles of cell death-inducing DFF45-like effector B and perilipin 2 in controlling hepatic VLDL lipidation,” The Journal of Lipid Research, vol. 53, no. 9, pp. 1877–1889, 2012.
[109]
U. Danesch, W. Hoeck, and G. M. Ringold, “Cloning and transcriptional regulation of a novel adipocyte-specific gene, FSP27. CAAT-enhancer-binding protein (C/EBP) and C/EBP-like proteins interact with sequences required for differentiation-dependent expression,” Journal of Biological Chemistry, vol. 267, no. 10, pp. 7185–7193, 1992.
[110]
K. Matsusue, T. Kusakabe, T. Noguchi et al., “Hepatic steatosis in leptin-deficient mice is promoted by the PPARγ target gene Fsp27,” Cell Metabolism, vol. 7, no. 4, pp. 302–311, 2008.
[111]
S. Yu, K. Matsusue, P. Kashireddy et al., “Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor γ1 (PPARγ1) overexpression,” Journal of Biological Chemistry, vol. 278, no. 1, pp. 498–505, 2003.
[112]
N. Guillén, M. A. Navarro, C. Arnal et al., “Microarray analysis of hepatic gene expression identifies new genes involved in steatotic liver,” Physiological Genomics, vol. 37, no. 3, pp. 187–198, 2009.
[113]
F. Yu, L. Su, S. Ji, et al., “Inhibition of hepatic stellate cell activation and liver fibrosis by fat-specific protein 27,” Molecular and Cellular Biochemistry, vol. 369, no. 1-2, pp. 35–43, 2012.
[114]
A. J. Hoy, C. R. Bruce, S. M. Turpin, A. J. Morris, M. A. Febbraio, and M. J. Watt, “Adipose triglyceride lipase-null mice are resistant to high-fat diet-induced insulin resistance despite reduced energy expenditure and ectopic lipid accumulation,” Endocrinology, vol. 152, no. 1, pp. 48–58, 2011.
[115]
J. W. Wu, S. P. Wang, F. Alvarez et al., “Deficiency of liver adipose triglyceride lipase in mice causes progressive hepatic steatosis,” Hepatology, vol. 54, no. 1, pp. 122–132, 2011.
[116]
S. M. Turpin, A. J. Hoy, R. D. Brown et al., “Adipose triacylglycerol lipase is a major regulator of hepatic lipid metabolism but not insulin sensitivity in mice,” Diabetologia, vol. 54, no. 1, pp. 146–156, 2011.
[117]
K. T. Ong, M. T. Mashek, S. Y. Bu, and D. G. Mashek, “Hepatic ATGL knockdown uncouples glucose intolerance from liver TAG accumulation,” The FASEB Journal, vol. 27, no. 1, pp. 313–321, 2013.
[118]
P. Jha, T. Claudel, A. Baghdasaryan, et al., “Role of adipose triglyceride lipase (PNPLA2) in protection from hepatic inflammation in mouse models of steatohepatitis and endotoxemia,” Hepatology, vol. 59, no. 3, pp. 858–869, 2014.
[119]
A. Natali, A. Gastaldelli, S. Camastra, et al., “Metabolic consequences of adipose triglyceride lipase deficiency in humans: an in vivo study in patients with neutral lipid storage disease with myopathy,” The Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 9, pp. E1540–E1548, 2013.
[120]
B. N. Reid, G. P. Ables, O. A. Otlivanchik et al., “Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis,” Journal of Biological Chemistry, vol. 283, no. 19, pp. 13087–13099, 2008.
[121]
K. T. Ong, M. T. Mashek, S. Y. Bu, A. S. Greenberg, and D. G. Mashek, “Adipose triglyceride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning,” Hepatology, vol. 53, no. 1, pp. 116–126, 2011.
[122]
T. C. Leone, C. J. Weinheimer, and D. P. Kelly, “A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response: the PPARα-null mouse as a model of fatty acid oxidation disorders,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 13, pp. 7473–7478, 1999.
[123]
K. Harada, W.-J. Shen, S. Patel et al., “Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice,” American Journal of Physiology—Endocrinology and Metabolism, vol. 285, no. 6, pp. E1182–E1195, 2003.
[124]
S. J. Yeaman, “Hormone-sensitive lipase—new roles for an old enzyme,” Biochemical Journal, vol. 379, no. 1, pp. 11–22, 2004.
[125]
S.-Y. Park, H.-J. Kim, S. Wang et al., “Hormone-sensitive lipase knockout mice have increased hepatic insulin sensitivity and are protected from short-term diet-induced insulin resistance in skeletal muscle and heart,” American Journal of Physiology—Endocrinology and Metabolism, vol. 289, no. 1, pp. E30–E39, 2005.
[126]
P. J. Voshol, G. Haemmerle, D. M. Ouwens et al., “Increased hepatic insulin sensitivity together with decreased hepatic triglyceride stores in hormone-sensitive lipase-deficient mice,” Endocrinology, vol. 144, no. 8, pp. 3456–3462, 2003.
[127]
U. Taschler, F. P. W. Radner, C. Heier et al., “Monoglyceride lipase deficiency in mice impairs lipolysis and attenuates diet-induced insulin resistance,” Journal of Biological Chemistry, vol. 286, no. 20, pp. 17467–17477, 2011.
[128]
Z. Cao, M. M. Mulvihill, P. Mukhopadhyay, et al., “Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice,” Gastroenterology, vol. 144, no. 4, pp. 808.e15–817.e15, 2013.
[129]
S. Romeo, J. Kozlitina, C. Xing et al., “Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease,” Nature Genetics, vol. 40, no. 12, pp. 1461–1465, 2008.
[130]
V. Nobili, G. Bedogni, B. Donati, A. Alisi, and L. Valenti, “The I148M variant of PNPLA3 reduces the response to docosahexaenoic acid in children with non-alcoholic fatty liver disease,” Journal of Medicinal Food, vol. 16, no. 10, pp. 957–960, 2013.
[131]
Y. Rotman, C. Koh, J. M. Zmuda, D. E. Kleiner, and T. J. Liang, “The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease,” Hepatology, vol. 52, no. 3, pp. 894–903, 2010.
[132]
S. Sookoian, G. O. Casta？o, A. L. Burgue？o, T. F. Gianotti, M. S. Rosselli, and C. J. Pirola, “A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity,” Journal of Lipid Research, vol. 50, no. 10, pp. 2111–2116, 2009.
[133]
S. Sookoian and C. J. Pirola, “Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease,” Hepatology, vol. 53, no. 6, pp. 1883–1894, 2011.
[134]
L. Valenti, A. Al-Serri, A. K. Daly et al., “Homozygosity for the patatin-like phospholipase-3/adiponutrin i148m polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease,” Hepatology, vol. 51, no. 4, pp. 1209–1217, 2010.
[135]
L. Valenti, P. Dongiovanni, S. Ginanni Corradini, M. A. Burza, and S. Romeo, “PNPLA3 I148M variant and hepatocellular carcinoma: a common genetic variant for a rare disease,” Digestive and Liver Disease, vol. 45, no. 8, pp. 619–624, 2013.
[136]
L. Valenti, P. Maggioni, A. Piperno, et al., “Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis,” World Journal of Gastroenterology, vol. 18, no. 22, pp. 2813–2820, 2012.
[137]
Y. Huang, S. He, J. Z. Li et al., “A feed-forward loop amplifies nutritional regulation of PNPLA3,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 17, pp. 7892–7897, 2010.
[138]
M. Hoekstra, Z. Li, J. K. Kruijt, M. V. Eck, T. J. C. V. Berkel, and J. Kuiper, “The expression level of non-alcoholic fatty liver disease-related gene PNPLA3 in hepatocytes is highly influenced by hepatic lipid status,” Journal of Hepatology, vol. 52, no. 2, pp. 244–251, 2010.
[139]
W. Chen, B. Chang, L. Li, and L. Chan, “Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease,” Hepatology, vol. 52, no. 3, pp. 1134–1142, 2010.
[140]
Y. Huang, J. C. Cohen, and H. H. Hobbs, “Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease,” Journal of Biological Chemistry, vol. 286, no. 43, pp. 37085–37093, 2011.
[141]
J. Z. Li, Y. Huang, R. Karaman, et al., “Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis,” The Journal of Clinical Investigation, vol. 122, no. 11, pp. 4130–4144, 2012.
[142]
S. Mudaliar, R. R. Henry, A. J. Sanyal, et al., “Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease,” Gastroenterology, vol. 145, no. 3, pp. 574.e1–582.e1, 2013.
[143]
M. Péterfy, J. Phan, P. Xu, and K. Reue, “Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin,” Nature Genetics, vol. 27, no. 1, pp. 121–124, 2001.
[144]
K. Reue, P. Xu, X.-P. Wang, and B. G. Slavin, “Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene,” Journal of Lipid Research, vol. 41, no. 7, pp. 1067–1076, 2000.
[145]
L. S. Csaki, J. R. Dwyer, X. Li, et al., “Lipin-1 and lipin-3 together determine adiposity in vivo,” Molecular Metabolism, vol. 3, no. 2, pp. 145–154, 2014.
