‘Micro‐managers’ of hepatic lipid metabolism and NAFLD

Advanced Review

Wei Liu, Hongchao Cao, Jun Yan, Ruimin Huang, Hao Ying

Published Online: Jul 21 2015

DOI: 10.1002/wrna.1295

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

Nonalcoholic fatty liver disease (NAFLD) is tightly associated with insulin resistance, type 2 diabetes, and obesity. As the defining feature of NAFLD, hepatic steatosis develops as a consequence of metabolic dysregulation of de novo lipogenesis, fatty acid uptake, fatty acid oxidation, and triglycerides (TG) export. MicroRNAs (miRNAs), a class of endogenous small noncoding RNAs, play critical roles in various biological processes through regulating gene expression at post‐transcriptional level. A growing body of evidence suggests that miRNAs not only maintain hepatic TG homeostasis under physiological condition, but also participate in the pathogenesis of NAFLD. In this review, we focus on the current knowledge of the hepatic miRNAs associated with the development of liver steatosis and the regulatory mechanisms involved, which might be helpful to further understand the nature of NAFLD and provide a sound scientific basis for the drug development. WIREs RNA 2015, 6:581–593. doi: 10.1002/wrna.1295 This article is categorized under: RNA in Disease and Development > RNA in Disease

Important pathways that maintain hepatic TG homeostasis. Important metabolic pathways that maintain hepatic TG homeostasis are shown, including de novo lipogenesis, fatty acid uptake, fatty acid oxidation, fatty acid esterification, and TG export. ACC, acetyl CoA carboxylase; ACL, ATP‐citrate lyase; ApoB, apolipoprotein B; ChREBP, carbohydrate response element binding protein; FA, fatty acid; FABP, fatty acid binding protein; FASN, fatty acid synthase; FATP, fatty acid transporter; KB, ketone bodies; LPL, lipoprotein lipase; LXRα, liver X receptor alpha; MTTP, microsomal triglyceride transfer protein; NEFA, nonesterified fatty acid; SCD1, stearoyl‐CoA desaturase‐1; SREBP‐1c, sterol responsive element binding protein‐1c; TG, triglycerides; VLDL, very low density lipoprotein.

[ Normal View | Magnified View ]

References

Lagos‐Quintana, M, Rauhut, R, Lendeckel, W, Tuschl, T. Identification of novel genes coding for small expressed RNAs. Science 2001, 294:853–858.
He, L, Hannon, GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004, 5:522–531.
Lewis, BP, Burge, CB, Bartel, DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005, 120:15–20.
Alvarez‐Garcia, I, Miska, EA. MicroRNA functions in animal development and human disease. Development 2005, 132:4653–4662.
Shenoy, A, Blelloch, RH. Regulation of microRNA function in somatic stem cell proliferation and differentiation. Nat Rev Mol Cell Biol 2014, 15:565–576.
Rottiers, V, Naar, AM. MicroRNAs in metabolism and metabolic disorders. Nat Rev Mol Cell Biol 2012, 13:239–250.
Roy, S, Sen, CK. MiRNA in innate immune responses: novel players in wound inflammation. Physiol Genomics 2011, 43:557–565.
Yang, W, Lee, DY, Ben‐David, Y. The roles of microRNAs in tumorigenesis and angiogenesis. Int J Physiol Pathophysiol Pharmacol 2011, 3:140–155.
Blachier, M, Leleu, H, Peck‐Radosavljevic, M, Valla, DC, Roudot‐Thoraval, F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol 2013, 58:593–608.
Cohen, JC, Horton, JD, Hobbs, HH. Human fatty liver disease: old questions and new insights. Science 2011, 332:1519–1523.
Angulo, P. Nonalcoholic fatty liver disease. N Engl J Med 2002, 346:1221–1231.
Hebbard, L, George, J. Animal models of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2011, 8:35–44.
Sass, DA, Chang, P, Chopra, KB. Nonalcoholic fatty liver disease: a clinical review. Dig Dis Sci 2005, 50:171–180.
McCullough, AJ. Pathophysiology of nonalcoholic steatohepatitis. J Clin Gastroenterol 2006, 40(Suppl 1):S17–S29.
Kleiner, DE, Brunt, EM, Van Natta, M, Behling, C, Contos, MJ, Cummings, OW, Ferrell, LD, Liu, YC, Torbenson, MS, Unalp‐Arida, A, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005, 41:1313–1321.
Day, CP, James, OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998, 114:842–845.
Esau, C, Davis, S, Murray, SF, Yu, XX, Pandey, SK, Pear, M, Watts, L, Booten, SL, Graham, M, McKay, R, et al. miR‐122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 2006, 3:87–98.
Cheung, O, Puri, P, Eicken, C, Contos, MJ, Mirshahi, F, Maher, JW, Kellum, JM, Min, H, Luketic, VA, Sanyal, AJ. Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression. Hepatology 2008, 48:1810–1820.
Iliopoulos, D, Drosatos, K, Hiyama, Y, Goldberg, IJ, Zannis, VI. MicroRNA‐370 controls the expression of MicroRNA‐122 and Cpt1 alpha and affects lipid metabolism. J Lipid Res 2010, 51:1513–1523.
Horie, T, Nishino, T, Baba, O, Kuwabara, Y, Nakao, T, Nishiga, M, Usami, S, Izuhara, M, Sowa, N, Yahagi, N, et al. MicroRNA‐33 regulates sterol regulatory element‐binding protein 1 expression in mice. Nat Commun 2013, 4:2883.
Goedeke, L, Salerno, A, Ramirez, CM, Guo, L, Allen, RM, Yin, X, Langley, SR, Esau, C, Wanschel, A, Fisher, EA, et al. Long‐term therapeutic silencing of miR‐33 increases circulating triglyceride levels and hepatic lipid accumulation in mice. EMBO Mol Med 2014, 6:1133–1141.
Wang, XC, Zhan, XR, Li, XY, Yu, JJ, Liu, XM. MicroRNA‐185 regulates expression of lipid metabolism genes and improves insulin sensitivity in mice with non‐alcoholic fatty liver disease. World J Gastroenterol 2014, 20:17914–17923.
Zhong, D, Huang, G, Zhang, Y, Zeng, Y, Xu, Z, Zhao, Y, He, X, He, F. MicroRNA‐1 and microRNA‐206 suppress LXRalpha‐induced lipogenesis in hepatocytes. Cell Signal 2013, 25:1429–1437.
Zhong, D, Zhang, Y, Zeng, YJ, Gao, M, Wu, GZ, Hu, CJ, Huang, G, He, FT. MicroRNA‐613 represses lipogenesis in HepG2 cells by downregulating LXRalpha. Lipids Health Dis 2013, 12:32.
Miller, AM, Gilchrist, DS, Nijjar, J, Araldi, E, Ramirez, CM, Lavery, CA, Fernandez‐Hernando, C, McInnes, IB, Kurowska‐Stolarska, M. MiR‐155 has a protective role in the development of non‐alcoholic hepatosteatosis in mice. PLoS One 2013, 8:e72324.
Liu, W, Cao, H, Ye, C, Chang, C, Lu, M, Jing, Y, Zhang, D, Yao, X, Duan, Z, Xia, H, et al. Hepatic miR‐378 targets p110alpha and controls glucose and lipid homeostasis by modulating hepatic insulin signalling. Nat Commun 2014, 5:5684.
Vinciguerra, M, Sgroi, A, Veyrat‐Durebex, C, Rubbia‐Brandt, L, Buhler, LH, Foti, M. Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA‐21 up‐regulation in hepatocytes. Hepatology 2009, 49:1176–1184.
Ahn, J, Lee, H, Chung, CH, Ha, T. High fat diet induced downregulation of microRNA‐467b increased lipoprotein lipase in hepatic steatosis. Biochem Biophys Res Commun 2011, 414:664–669.
Mattis, AN, Song, GS, Hitchner, K, Kim, RY, Lee, AY, Sharma, AD, Malato, Y, McManus, MT, Esau, CC, Koller, E, et al. A screen in mice uncovers repression of lipoprotein lipase by MicroRNA‐29a as a mechanism for lipid distribution away from the liver. Hepatology 2015, 61:141–152.
Ahn, J, Lee, H, Jung, CH, Ha, T. Lycopene inhibits hepatic steatosis via microRNA‐21‐induced downregulation of fatty acid‐binding protein 7 in mice fed a high‐fat diet. Mol Nutr Food Res 2012, 56:1665–1674.
Zheng, L, Lv, GC, Sheng, JF, Yang, YD. Effect of miRNA‐10b in regulating cellular steatosis level by targeting PPAR‐alpha expression, a novel mechanism for the pathogenesis of NAFLD. J Gastroenterol Hepatol 2010, 25:156–163.
Li, B, Zhang, Z, Zhang, H, Quan, K, Lu, Y, Cai, D, Ning, G. Aberrant miR199a‐5p/caveolin1/PPARalpha axis in hepatic steatosis. J Mol Endocrinol 2014, 53:393–403.
Gerin, I, Clerbaux, LA, Haumont, O, Lanthier, N, Das, AK, Burant, CF, Leclercq, IA, MacDougald, OA, Bommer, GT. Expression of miR‐33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J Biol Chem 2010, 285:33652–33661.
Davalos, A, Goedeke, L, Smibert, P, Ramirez, CM, Warrier, NP, Andreo, U, Cirera‐Salinas, D, Rayner, K, Suresh, U, Pastor‐Pareja, JC, et al. miR‐33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci USA 2011, 108:9232–9237.
Goedeke, L, Vales‐Lara, FM, Fenstermaker, M, Cirera‐Salinas, D, Chamorro‐Jorganes, A, Ramirez, CM, Mattison, JA, de Cabo, R, Suarez, Y, Fernandez‐Hernando, C. A regulatory role for microRNA 33* in controlling lipid metabolism gene expression. Mol Cell Biol 2013, 33:2339–2352.
Carrer, M, Liu, N, Grueter, CE, Williams, AH, Frisard, MI, Hulver, MW, Bassel‐Duby, R, Olson, EN. Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378(star). Proc Natl Acad Sci USA 2012, 109:15330–15335.
Tsai, WC, Hsu, SD, Hsu, CS, Lai, TC, Chen, SJ, Shen, R, Huang, Y, Chen, HC, Lee, CH, Tsai, TF, et al. MicroRNA‐122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest 2012, 122:2884–2897.
Soh, J, Iqbal, J, Queiroz, J, Fernandez‐Hernando, C, Hussain, MM. MicroRNA‐30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion. Nat Med 2013, 19:892–900.
Chalasani, N, Younossi, Z, Lavine, JE, Diehl, AM, Brunt, EM, Cusi, K, Charlton, M, Sanyal, AJ. The diagnosis and management of non‐alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012, 55:2005–2023.
Hur, W, Lee, JH, Kim, SW, Kim, JH, Bae, SH, Kim, M, Hwang, D, Kim, YS, Park, T, Um, SJ, et al. Downregulation of microRNA‐451 in non‐alcoholic steatohepatitis inhibits fatty acid‐induced proinflammatory cytokine production through the AMPK/AKT pathway. Int J Biochem Cell Biol 2015, 64:265–276.
Jin, X, Ye, YF, Chen, SH, Yu, CH, Liu, J, Li, YM. MicroRNA expression pattern in different stages of nonalcoholic fatty liver disease. Dig Liver Dis 2009, 41:289–297.
Roderburg, C, Luedde, T. Circulating microRNAs as markers of liver inflammation, fibrosis and cancer. J Hepatol 2014, 61:1434–1437.
Gori, M, Arciello, M, Balsano, C. MicroRNAs in nonalcoholic fatty liver disease: novel biomarkers and prognostic tools during the transition from steatosis to hepatocarcinoma. Biomed Res Int 2014, 2014:741465.
Strable, MS, Ntambi, JM. Genetic control of de novo lipogenesis: role in diet‐induced obesity. Crit Rev Biochem Mol Biol 2010, 45:199–214.
Lodhi, IJ, Wei, X, Semenkovich, CF. Lipoexpediency: de novo lipogenesis as a metabolic signal transmitter. Trends Endocrinol Metab 2011, 22:1–8.
Foufelle, F, Ferre, P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein‐1c. Biochem J 2002, 366:377–391.
Ulven, SM, Dalen, KT, Gustafsson, JA, Nebb, HI. LXR is crucial in lipid metabolism. Prostaglandins Leukot Essent Fatty Acids 2005, 73:59–63.
Chen, G, Liang, G, Ou, J, Goldstein, JL, Brown, MS. Central role for liver X receptor in insulin‐mediated activation of Srebp‐1c transcription and stimulation of fatty acid synthesis in liver. Proc Natl Acad Sci USA 2004, 101:11245–11250.
Dentin, R, Pegorier, JP, Benhamed, F, Foufelle, F, Ferre, P, Fauveau, V, Magnuson, MA, Girard, J, Postic, C. Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP‐1c on glycolytic and lipogenic gene expression. J Biol Chem 2004, 279:20314–20326.
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.
Ameer, F, Scandiuzzi, L, Hasnain, S, Kalbacher, H, Zaidi, N. De novo lipogenesis in health and disease. Metabolism 2014, 63:895–902.
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, 115:1343–1351.
Krutzfeldt, J, Rajewsky, N, Braich, R, Rajeev, KG, Tuschl, T, Manoharan, M, Stoffel, M. Silencing of microRNAs in vivo with `antagomirs`. Nature 2005, 438:685–689.
Vickers, KC, Remaley, AT. MicroRNAs in atherosclerosis and lipoprotein metabolism. Curr Opin Endocrinol Diabetes Obes 2010, 17:150–155.
Lagos‐Quintana, M, Rauhut, R, Yalcin, A, Meyer, J, Lendeckel, W, Tuschl, T. Identification of tissue‐specific microRNAs from mouse. Curr Biol 2002, 12:735–739.
Fernandez‐Hernando, C, Moore, KJ. MicroRNA modulation of cholesterol homeostasis. Arterioscler Thromb Vasc Biol 2011, 31:2378–2382.
Najafi‐Shoushtari, SH, Kristo, F, Li, Y, Shioda, T, Cohen, DE, Gerszten, RE, Naar, AM. MicroRNA‐33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 2010, 328:1566–1569.
Takahashi, Y, Forrest, AR, Maeno, E, Hashimoto, T, Daub, CO, Yasuda, J. MiR‐107 and MiR‐185 can induce cell cycle arrest in human non small cell lung cancer cell lines. PLoS One 2009, 4:e6677.
Xiang, Y, Ma, N, Wang, D, Zhang, Y, Zhou, J, Wu, G, Zhao, R, Huang, H, Wang, X, Qiao, Y, et al. MiR‐152 and miR‐185 co‐contribute to ovarian cancer cells cisplatin sensitivity by targeting DNMT1 directly: a novel epigenetic therapy independent of decitabine. Oncogene 2014, 33:378–386.
Yang, M, Liu, W, Pellicane, C, Sahyoun, C, Joseph, BK, Gallo‐Ebert, C, Donigan, M, Pandya, D, Giordano, C, Bata, A, et al. Identification of miR‐185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake. J Lipid Res 2014, 55:226–238.
Li, X, Chen, YT, Josson, S, Mukhopadhyay, NK, Kim, J, Freeman, MR, Huang, WC. MicroRNA‐185 and 342 inhibit tumorigenicity and induce apoptosis through blockade of the SREBP metabolic pathway in prostate cancer cells. PLoS One 2013, 8:e70987.
Jiang, S, Zhang, LF, Zhang, HW, Hu, S, Lu, MH, Liang, S, Li, B, Li, Y, Li, D, Wang, ED, et al. A novel miR‐155/miR‐143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells. EMBO J 2012, 31:1985–1998.
Zhang, P, Bill, K, Liu, J, Young, E, Peng, T, Bolshakov, S, Hoffman, A, Song, Y, Demicco, EG, Terrada, DL, et al. MiR‐155 is a liposarcoma oncogene that targets casein kinase‐1alpha and enhances beta‐catenin signaling. Cancer Res 2012, 72:1751–1762.
Li, S, Chen, T, Zhong, Z, Wang, Y, Li, Y, Zhao, X. microRNA‐155 silencing inhibits proliferation and migration and induces apoptosis by upregulating BACH1 in renal cancer cells. Mol Med Rep 2012, 5:949–954.
Wong, RH, Sul, HS. Insulin signaling in fatty acid and fat synthesis: a transcriptional perspective. Curr Opin Pharmacol 2010, 10:684–691.
Timlin, MT, Parks, EJ. Temporal pattern of de novo lipogenesis in the postprandial state in healthy men. Am J Clin Nutr 2005, 81:35–42.
Leavens, KF, Birnbaum, MJ. Insulin signaling to hepatic lipid metabolism in health and disease. Crit Rev Biochem Mol Biol 2011, 46:200–215.
Postic, C, Girard, J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 2008, 118:829–838.
Taniguchi, CM, Emanuelli, B, Kahn, CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 2006, 7:85–96.
Kadowaki, T, Ueki, K, Yamauchi, T, Kubota, N. SnapShot: Insulin signaling pathways. Cell 2012, 148:624–624.e621.
Chattopadhyay, M, Selinger, ES, Ballou, LM, Lin, RZ. Ablation of PI3K p110‐alpha prevents high‐fat diet‐induced liver steatosis. Diabetes 2011, 60:1483–1492.
Maehama, T, Dixon, JE. PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol 1999, 9:125–128.
Watanabe, S, Horie, Y, Suzuki, A. Hepatocyte‐specific Pten‐deficient mice as a novel model for nonalcoholic steatohepatitis and hepatocellular carcinoma. Hepatol Res 2005, 33:161–166.
Lafontan, M, Langin, D. Lipolysis and lipid mobilization in human adipose tissue. Prog Lipid Res 2009, 48:275–297.
Fielding, BA, Callow, J, Owen, RM, Samra, JS, Matthews, DR, Frayn, KN. Postprandial lipemia: the origin of an early peak studied by specific dietary fatty acid intake during sequential meals. Am J Clin Nutr 1996, 63:36–41.
Heeren, J, Niemeier, A, Merkel, M, Beisiegel, U. Endothelial‐derived lipoprotein lipase is bound to postprandial triglyceride‐rich lipoproteins and mediates their hepatic clearance in vivo. J Mol Med (Berl) 2002, 80:576–584.
Musso, G, Gambino, R, Cassader, M. Recent insights into hepatic lipid metabolism in non‐alcoholic fatty liver disease (NAFLD). Prog Lipid Res 2009, 48:1–26.
Karpe, F, Dickmann, JR, Frayn, KN. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes 2011, 60:2441–2449.
Jacome‐Sosa, MM, Parks, EJ. Fatty acid sources and their fluxes as they contribute to plasma triglyceride concentrations and fatty liver in humans. Curr Opin Lipidol 2014, 25:213–220.
Davies, BS, Beigneux, AP, Fong, LG, Young, SG. New wrinkles in lipoprotein lipase biology. Curr Opin Lipidol 2012, 23:35–42.
Pardina, E, Baena‐Fustegueras, JA, Llamas, R, Catalan, R, Galard, R, Lecube, A, Fort, JM, Llobera, M, Allende, H, Vargas, V, et al. Lipoprotein lipase expression in livers of morbidly obese patients could be responsible for liver steatosis. Obes Surg 2009, 19:608–616.
Kim, JK, Fillmore, JJ, Chen, Y, Yu, C, Moore, IK, Pypaert, M, Lutz, EP, Kako, Y, Velez‐Carrasco, W, Goldberg, IJ, et al. Tissue‐specific overexpression of lipoprotein lipase causes tissue‐specific insulin resistance. Proc Natl Acad Sci USA 2001, 98:7522–7527.
Chiu, HK, Qian, K, Ogimoto, K, Morton, GJ, Wisse, BE, Agrawal, N, McDonald, TO, Schwartz, MW, Dichek, HL. Mice lacking hepatic lipase are lean and protected against diet‐induced obesity and hepatic steatosis. Endocrinology 2010, 151:993–1001.
Jiang, H, Zhang, G, Wu, JH, Jiang, CP. Diverse roles of miR‐29 in cancer (review). Oncol Rep 2014, 31:1509–1516.
Storch, J, Corsico, B. The emerging functions and mechanisms of mammalian fatty acid‐binding proteins. Annu Rev Nutr 2008, 28:73–95.
Halliwell, KJ, Fielding, BA, Samra, JS, Humphreys, SM, Frayn, KN. Release of individual fatty acids from human adipose tissue in vivo after an overnight fast. J Lipid Res 1996, 37:1842–1848.
Frayn, KN, Arner, P, Yki‐Jarvinen, H. Fatty acid metabolism in adipose tissue, muscle and liver in health and disease. Essays Biochem 2006, 42:89–103.
Eaton, S, Bartlett, K, Pourfarzam, M. Mammalian mitochondrial beta‐oxidation. Biocheml J 1996, 320:345–357.
Gibbons, GF, Islam, K, Pease, RJ. Mobilisation of triacylglycerol stores. Biochim Biophys Acta 2000, 1483:37–57.
Reddy, JK, Hashimoto, T. Peroxisomal beta‐oxidation and peroxisome proliferator‐activated receptor alpha: an adaptive metabolic system. Annu Rev Nutr 2001, 21:193–230.
Kersten, S, Seydoux, J, Peters, JM, Gonzalez, FJ, Desvergne, B, Wahli, W. Peroxisome proliferator‐activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 1999, 103:1489–1498.
Leone, TC, Weinheimer, CJ, Kelly, DP. A critical role for the peroxisome proliferator‐activated receptor alpha (PPAR alpha) in the cellular fasting response: the PPAR alpha‐ mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci USA 1999, 96:7473–7478.
Hashimoto, T, Cook, WS, Qi, C, Yeldandi, AV, Reddy, JK, Rao, MS. Defect in peroxisome proliferator‐activated receptor alpha‐inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting. J Biol Chem 2000, 275:28918–28928.
Abu‐Elheiga, L, Oh, WK, Kordari, P, Wakil, SJ. Acetyl‐CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high‐fat/high‐carbohydrate diets. Proc Natl Acad Sci USA 2003, 100:10207–10212.
Zhao, C, Zhang, T, Shi, Z, Ding, H, Ling, X. MicroRNA‐518d regulates PPARalpha protein expression in the placentas of females with gestational diabetes mellitus. Mol Med Rep 2014, 9:2085–2090.
Sahasrabuddhe, NA, Huang, TC, Ahmad, S, Kim, MS, Yang, Y, Ghosh, B, Leach, SD, Gowda, H, Somani, BL, Chaerkady, R, et al. Regulation of PPAR‐alpha pathway by Dicer revealed through proteomic analysis. J Proteomics 2014, 108:306–315.
Fernandez‐Rojo, MA, Gongora, M, Fitzsimmons, RL, Martel, N, Martin, SD, Nixon, SJ, Brooks, AJ, Ikonomopoulou, MP, Martin, S, Lo, HP, et al. Caveolin‐1 is necessary for hepatic oxidative lipid metabolism: evidence for crosstalk between caveolin‐1 and bile acid signaling. Cell Rep 2013, 4:238–247.
Lin, JD, Handschin, C, Spiegelman, BM. Metabolic control through the PGC‐1 family of transcription coactivators. Cell Metab 2005, 1:361–370.
Abu‐Elheiga, L, Matzuk, MM, Abo‐Hashema, KAH, Wakil, SJ. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl‐CoA carboxylase 2. Science 2001, 291:2613–2616.
Tiwari, S, Siddiqi, SA. Intracellular trafficking and secretion of VLDL. Arterioscler Thromb Vasc Biol 2012, 32:1079–1086.
Raabe, M, Veniant, MM, Sullivan, MA, Zlot, CH, Bjorkegren, J, Nielsen, LB, Wong, JS, Hamilton, RL, Young, SG. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue‐specific knockout mice. J Clin Invest 1999, 103:1287–1298.
Chen, Z, Fitzgerald, RL, Averna, MR, Schonfeld, G. A targeted apolipoprotein B‐38.9‐producing mutation causes fatty livers in mice due to the reduced ability of apolipoprotein B‐38.9 to transport triglycerides. J Biol Chem 2000, 275:32807–32815.
Schonfeld, G, Lin, X, Yue, P. Familial hypobetalipoproteinemia: genetics and metabolism. Cell Mol Life Sci 2005, 62:1372–1378.
Berriot‐Varoqueaux, N, Aggerbeck, LP, Samson‐Bouma, M, Wetterau, JR. The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. Annu Rev Nutr 2000, 20:663–697.
Yang, Y, Cao, J, Shi, Y. Identification and characterization of a gene encoding human LPGAT1, an endoplasmic reticulum‐associated lysophosphatidylglycerol acyltransferase. J Biol Chem 2004, 279:55866–55874.
Mangravite, LM, Dawson, K, Davis, RR, Gregg, JP, Krauss, RM. Fatty acid desaturase regulation in adipose tissue by dietary composition is independent of weight loss and is correlated with the plasma triacylglycerol response. Am J Clin Nutr 2007, 86:759–767.
van Rooij, E, Purcell, AL, Levin, AA. Developing microRNA therapeutics. Circ Res 2012, 110:496–507.
Shah, N, Nelson, JE, Kowdley, KV. MicroRNAs in liver disease: bench to bedside. J Clin Exp Hepatol 2013, 3:231–242.
Qiu, Z, Dai, Y. Roadmap of miR‐122‐related clinical application from bench to bedside. Expert Opin Investig Drugs 2014, 23:347–355.
van Rooij, E, Kauppinen, S. Development of microRNA therapeutics is coming of age. EMBO Mol Med 2014, 6:851–864.
Agostini, M, Knight, RA. miR‐34: from bench to bedside. Oncotarget 2014, 5:872–881.
Lanford, RE, Hildebrandt‐Eriksen, ES, Petri, A, Persson, R, Lindow, M, Munk, ME, Kauppinen, S, Orum, H. Therapeutic silencing of microRNA‐122 in primates with chronic hepatitis C virus infection. Science 2010, 327:198–201.
Rayner, KJ, Esau, CC, Hussain, FN, McDaniel, AL, Marshall, SM, van Gils, JM, Ray, TD, Sheedy, FJ, Goedeke, L, Liu, X, et al. Inhibition of miR‐33a/b in non‐human primates raises plasma HDL and lowers VLDL triglycerides. Nature 2011, 478:404–407.
Montgomery, RL, Hullinger, TG, Semus, HM, Dickinson, BA, Seto, AG, Lynch, JM, Stack, C, Latimer, PA, Olson, EN, van Rooij, E. Therapeutic inhibition of miR‐208a improves cardiac function and survival during heart failure. Circulation 2011, 124:1537–1547.
Liu, G, Friggeri, A, Yang, Y, Milosevic, J, Ding, Q, Thannickal, VJ, Kaminski, N, Abraham, E. miR‐21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med 2010, 207:1589–1597.
Janssen, HL, Reesink, HW, Lawitz, EJ, Zeuzem, S, Rodriguez‐Torres, M, Patel, K, van der Meer, AJ, Patick, AK, Chen, A, Zhou, Y, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med 2013, 368:1685–1694.

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

‘Micro‐managers’ of hepatic lipid metabolism and NAFLD

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox