Hepatic Lipid Metabolism

  • Jiansheng Huang
  • Jayme Borensztajn
  • Janardan K. Reddy
Part of the Molecular Pathology Library book series (MPLB, volume 5)


The liver is a major regulator of lipid metabolism in the body. It plays a central role in the synthesis and degradation (oxidation) of fatty acids. Fatty acids serve as an important source of energy as well as energy storage for many organisms and are also pivotal for a variety of biological processes, including the synthesis of cellular membrane lipids and generation of lipid-containing messengers involved in signal transduction [1]. Fatty acids can generally be stored efficiently as non-toxic triglycerides (triacylglycerols/fat), which generate more than twice as much energy, for the same mass, as do carbohydrates or proteins. Accordingly, liver is a key player in energy homeostasis: first, as it converts excess dietary glucose into fatty acids that are then exported to other tissues for storage as triglycerides as lipid droplets [2]; second, under conditions of increase in synthesis and decreased oxidation of fatty acids the liver contributes to the progressive accumulation of excess unspent energy in the form of energy-dense triglycerides in adipocytes of adipose tissue, which provide virtually limitless capacity to store energy and finally, under chronic energy over-load situations the liver may serve as a surrogate reservoir for storing considerable quantities of excess fat, leading to the development of hepatic steatosis and steatohepatitis [3].


Lipid Droplet Fatty Acid Oxidation Hepatic Steatosis Microsomal Triglyceride Transfer Protein Hepatic Lipid Metabolism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by NIH Grant DK083163 (J.K.R).


  1. 1.
    Eyster KM. The membrane and lipids as integral participants in signal transduction: lipid signal transduction for the non-lipid biochemist. Adv Physiol Educ. 2007;31:5–16.PubMedGoogle Scholar
  2. 2.
    Hostetler HA, Huang H, Kier AB, et al. Glucose directly links to lipid metabolism through high affinity interaction with peroxisome proliferator-activated receptor alpha. J Biol Chem. 2008;283:2246–54.PubMedGoogle Scholar
  3. 3.
    Busetto L. Visceral obesity and the metabolic syndrome: effects of weight loss. Nutr Metab Cardiovasc Dis. 2001;11:195–204.PubMedGoogle Scholar
  4. 4.
    Reddy JK, Hashimoto T. Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annu Rev Nutr. 2001;21:193–230.PubMedGoogle Scholar
  5. 5.
    Mensenkamp AR, Havekes LM, Romijn JA, et al. Hepatic steatosis and very low density lipoprotein secretion: the involvement of apolipoprotein E. J Hepatol. 2001;35:816–22.PubMedGoogle Scholar
  6. 6.
    Zimmermann R, Lass A, Haemmerle G, et al. Fate of fat: the role of adipose triglyceride lipase in lipolysis. Biochim Biophys Acta. 2009;1791:494–500.PubMedGoogle Scholar
  7. 7.
    Schweiger M, Schreiber R, Haemmerle G, et al. Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism. J Biol Chem. 2006;281:40236–41.PubMedGoogle Scholar
  8. 8.
    Brasaemle DL. Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis. J Lipid Res. 2007;48:2547–59.PubMedGoogle Scholar
  9. 9.
    Holm C. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Biochem Soc Trans. 2003;31:1120–4.PubMedGoogle Scholar
  10. 10.
    Wang S, Soni KG, Semache M, et al. Lipolysis and the integrated physiology of lipid energy metabolism. Mol Genet Metab. 2008;95:117–26.PubMedGoogle Scholar
  11. 11.
    Shen WJ, Sridhar K, Bernlohr DA, et al. Interaction of rat hormone-sensitive lipase with adipocyte lipid-binding protein. Proc Natl Acad Sci U S A. 1999;96:5528–32.PubMedGoogle Scholar
  12. 12.
    Wang H, Eckel RH. Lipoprotein lipase: from gene to obesity. Am J Physiol Endocrinol Metab. 2009;297:E271–88.PubMedGoogle Scholar
  13. 13.
    Cianflone K, Paglialunga S, Roy C. Intestinally derived lipids: metabolic regulation and consequences – an overview. Atheroscler Suppl. 2008;9:63–8.PubMedGoogle Scholar
  14. 14.
    Stahl A. A current review of fatty acid transport proteins (SLC27). Pflugers Arch. 2004;447:722–7.PubMedGoogle Scholar
  15. 15.
    Guo W, Huang N, Cai J, et al. Fatty acid transport and metabolism in HepG2 cells. Am J Physiol Gastrointest Liver Physiol. 2006;290:G528–34.PubMedGoogle Scholar
  16. 16.
    Pohl J, Ring A, Hermann T, et al. Role of FATP in parenchymal cell fatty acid uptake. Biochim Biophys Acta. 2004;1686:1–6.PubMedGoogle Scholar
  17. 17.
    Doege H, Baillie RA, Ortegon AM, et al. Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis. Gastroenterology. 2006;130:1245–58.PubMedGoogle Scholar
  18. 18.
    Wu Q, Ortegon AM, Tsang B, et al. FATP1 is an insulin-sensitive fatty acid transporter involved in diet-induced obesity. Mol Cell Biol. 2006;26:3455–67.PubMedGoogle Scholar
  19. 19.
    Abumrad N, Coburn C, Ibrahimi A. Membrane proteins implicated in long-chain fatty acid uptake by mammalian cells: CD36, FATP and FABPm. Biochim Biophys Acta. 1999;1441:4–13.PubMedGoogle Scholar
  20. 20.
    Yu KC, Cooper AD. Postprandial lipoproteins and atherosclerosis. Front Biosci. 2001;6:D332–54.PubMedGoogle Scholar
  21. 21.
    Arrese EL, Soulages JL. Insect fat body: energy, metabolism, and regulation. Annu Rev Entomol. 2010;55:207–25.PubMedGoogle Scholar
  22. 22.
    Ducharme NA, Bickel PE. Lipid droplets in lipogenesis and lipolysis. Endocrinology. 2008;149:942–9.PubMedGoogle Scholar
  23. 23.
    Walther TC, Farese Jr RV. The life of lipid droplets. Biochim Biophys Acta. 2009;1791:459–66.PubMedGoogle Scholar
  24. 24.
    Murphy S, Martin S, Parton RG. Lipid droplet-organelle interactions; sharing the fats. Biochim Biophys Acta. 2009;1791:441–7.PubMedGoogle Scholar
  25. 25.
    Zehmer JK, Huang Y, Peng G, et al. A role for lipid droplets in inter-membrane lipid traffic. Proteomics. 2009;9:914–21.PubMedGoogle Scholar
  26. 26.
    Gong J, Sun Z, Li P. CIDE proteins and metabolic disorders. Curr Opin Lipidol. 2009;20:121–6.PubMedGoogle Scholar
  27. 27.
    Wolins NE, Brasaemle DL, Bickel PE. A proposed model of fat packaging by exchangeable lipid droplet proteins. FEBS Lett. 2006;580:5484–91.PubMedGoogle Scholar
  28. 28.
    Kimmel AR, Brasaemle DL, McAndrews-Hill M, et al. Adoption of PERILIPIN as a unifying nomenclature for the mammalian PAT-family of intracellular lipid storage droplet proteins. J Lipid Res. 2010;51:468–71.PubMedGoogle Scholar
  29. 29.
    Straub BK, Herpel E, Singer S, et al. Lipid droplet-associated PAT-proteins show frequent and differential expression in neoplastic steatogenesis. Mod Pathol. 2010;23:480–92.PubMedGoogle Scholar
  30. 30.
    Wolins NE, Skinner JR, Schoenfish MJ, et al. Adipocyte protein S3–12 coats nascent lipid droplets. J Biol Chem. 2003;278:37713–21.PubMedGoogle Scholar
  31. 31.
    Hall AM, Brunt EM, Chen Z, et al. Dynamic and differential regulation of proteins that coat lipid droplets in fatty liver dystrophic mice. J Lipid Res. 2010;51:554–63.PubMedGoogle Scholar
  32. 32.
    Dalen KT, Ulven SM, Arntsen BM, et al. PPARalpha activators and fasting induce the expression of adipose differentiation-related protein in liver. J Lipid Res. 2006;47:931–43.PubMedGoogle Scholar
  33. 33.
    Hashimoto T, Cook WS, Qi C, et al. 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;275:28918–289128.PubMedGoogle Scholar
  34. 34.
    Kersten S, Seydoux J, Peters JM, et al. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest. 1999;103:1489–98.PubMedGoogle Scholar
  35. 35.
    Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci U S A. 1999;96:7473–8.PubMedGoogle Scholar
  36. 36.
    Skinner JR, Shew TM, Schwartz DM, et al. Diacylglycerol enrichment of endoplasmic reticulum or lipid droplets recruits perilipin 3/TIP47 during lipid storage and mobilization. J Biol Chem. 2009;284:30941–8.PubMedGoogle Scholar
  37. 37.
    Tansey JT, Sztalryd C, Hlavin EM, et al. The central role of perilipin a in lipid metabolism and adipocyte lipolysis. IUBMB Life. 2004;56:379–85.PubMedGoogle Scholar
  38. 38.
    Moore HP, Silver RB, Mottillo EP, et al. Perilipin targets a novel pool of lipid droplets for lipolytic attack by hormone-sensitive lipase. J Biol Chem. 2005;280:43109–20.PubMedGoogle Scholar
  39. 39.
    Shen WJ, Patel S, Miyoshi H, et al. Functional interaction of hormone-sensitive lipase and perilipin in lipolysis. J Lipid Res. 2009;50:2306–13.PubMedGoogle Scholar
  40. 40.
    Marcinkiewicz A, Gauthier D, Garcia A, et al. The phosphorylation of serine 492 of perilipin a directs lipid droplet fragmentation and dispersion. J Biol Chem. 2006;281:11901–9.PubMedGoogle Scholar
  41. 41.
    Zhang HH, Souza SC, Muliro KV, et al. Lipase-selective functional domains of perilipin A differentially regulate constitutive and protein kinase A-stimulated lipolysis. J Biol Chem. 2003;278:51535–42.PubMedGoogle Scholar
  42. 42.
    Fujii H, Ikura Y, Arimoto J, et al. Expression of perilipin and adipophilin in nonalcoholic fatty liver disease; relevance to oxidative injury and hepatocyte ballooning. J Atheroscler Thromb. 2009;16:893–901.PubMedGoogle Scholar
  43. 43.
    Traini M, Jessup W. Lipid droplets and adipose metabolism: a novel role for FSP27/CIDEC. Curr Opin Lipidol. 2009;20:147–9.PubMedGoogle Scholar
  44. 44.
    Le Lay S, Dugail I. Connecting lipid droplet biology and the metabolic syndrome. Prog Lipid Res. 2009;48:191–5.PubMedGoogle Scholar
  45. 45.
    Meex RC, Schrauwen P, Hesselink MK. Modulation of myocellular fat stores: lipid droplet dynamics in health and disease. Am J Physiol Regul Integr Comp Physiol. 2009;297:R913–24.PubMedGoogle Scholar
  46. 46.
    Kim JY, Liu K, Zhou S, et al. Assessment of fat-specific protein 27 in the adipocyte lineage suggests a dual role for FSP27 in adipocyte metabolism and cell death. Am J Physiol Endocrinol Metab. 2008;294:E654–67.PubMedGoogle Scholar
  47. 47.
    Liu K, Zhou S, Kim JY, et al. Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA. Am J Physiol Endocrinol Metab. 2009;297:E1395–413.PubMedGoogle Scholar
  48. 48.
    Olofsson SO, Boström P, Andersson L, et al. Triglyceride containing lipid droplets and lipid droplet-associated proteins. Curr Opin Lipidol. 2008;19:441–7.PubMedGoogle Scholar
  49. 49.
    Unger RH. Longevity, lipotoxicity and leptin: the adipocyte defense against feasting and famine. Biochimie. 2005;87:57–64.PubMedGoogle Scholar
  50. 50.
    Wanders RJ, Ferdinandusse S, Brites P, et al. Peroxisomes, lipid metabolism and lipotoxicity. Biochim Biophys Acta. 2010;1801:272–80.PubMedGoogle Scholar
  51. 51.
    Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:360–9.PubMedGoogle Scholar
  52. 52.
    Imanishi Y, Gerke V, Palczewski K. Retinosomes: new insights into intracellular managing of hydrophobic substances in lipid bodies. J Cell Biol. 2004;166:447–53.PubMedGoogle Scholar
  53. 53.
    Parks EJ. Changes in fat synthesis influenced by dietary macronutrient content. Proc Nutr Soc. 2002;61:281–6.PubMedGoogle Scholar
  54. 54.
    Kahn A. Transcriptional regulation by glucose in the liver. Biochimie. 1997;79:113–8.PubMedGoogle Scholar
  55. 55.
    Jiang G, Zhang BB. Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab. 2003;284:E671–8.PubMedGoogle Scholar
  56. 56.
    Wakil SJ, Abu-Elheiga LA. Fatty acid metabolism: target for metabolic syndrome. J Lipid Res. 2009;50:S138–43.PubMedGoogle Scholar
  57. 57.
    Chang SI, Hammes GG. Structure and mechanism of action of a multifunctional enzyme: fatty acid synthase. Acc Chem Res. 1990;23:363–9.Google Scholar
  58. 58.
    Rioux V, Catheline D, Legrand P. In rat hepatocytes, myristic acid occurs through lipogenesis, palmitic acid shortening and lauric acid elongation. Animal. 2007;1:820–6.PubMedGoogle Scholar
  59. 59.
    Wang Y, Jones Voy B, Urs S, et al. The human fatty acid synthase gene and de novo lipogenesis are coordinately regulated in human adipose tissue. J Nutr. 2004;134:1032–8.PubMedGoogle Scholar
  60. 60.
    Gutiérrez-Juárez R, Pocai A, Mulas C, et al. Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance. J Clin Invest. 2006;116:1686–95.PubMedGoogle Scholar
  61. 61.
    Aarsland A, Wolfe RR. Hepatic secretion of VLDL fatty acids during stimulated lipogenesis in men. J Lipid Res. 1998;39:1280–6.PubMedGoogle Scholar
  62. 62.
    Leonard AE, Pereira SL, Sprecher H, et al. Elongation of long-chain fatty acids. Prog Lipid Res. 2004;43:36–54.PubMedGoogle Scholar
  63. 63.
    Jump DB. Mammalian fatty acid elongases. Methods Mol Biol. 2009;579:375–89.PubMedGoogle Scholar
  64. 64.
    Guillou H, Zadravec D, Martin PG, et al. The key roles of elongases and desaturases in mammalian fatty acid metabolism: insights from transgenic mice. Prog Lipid Res. 2010;49:186–99.PubMedGoogle Scholar
  65. 65.
    Jakobsson A, Westerberg R, Jacobsson A. Fatty acid elongases in mammals: their regulation and roles in metabolism. Prog Lipid Res. 2006;45:237–49.PubMedGoogle Scholar
  66. 66.
    Stein Y, Shapiro B. Uptake and metabolism of triglycerides by the rat liver. J Lipid Res. 1960;1:326–31.PubMedGoogle Scholar
  67. 67.
    Davidson NO, Shelness GS. APOLIPOPROTEIN B: mRNA editing, lipoprotein assembly, and presecretory degradation. Annu Rev Nutr. 2000;20:169–93.PubMedGoogle Scholar
  68. 68.
    Anant S, Davidson NO. Identification and regulation of protein components of the apolipoprotein B mRNA editing enzyme. A complex event. Trends Cardiovasc Med. 2002;12:311–7.PubMedGoogle Scholar
  69. 69.
    Cano A, Ciaffoni F, Safwat GM, et al. Hepatic VLDL assembly is disturbed in a rat model of nonalcoholic fatty liver disease: is there a role for dietary coenzyme Q? J Appl Physiol. 2009;107:707–17.PubMedGoogle Scholar
  70. 70.
    Shelness GS, Sellers JA. Very-low-density lipoprotein assembly and secretion. Curr Opin Lipidol. 2001;12:151–7.PubMedGoogle Scholar
  71. 71.
    Ginsberg HN, Fisher EA. The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism. J Lipid Res. 2009;50:S162–6.PubMedGoogle Scholar
  72. 72.
    Hussain MM, Iqbal J, Anwar K, et al. Microsomal triglyceride transfer protein: a multifunctional protein. Front Biosci. 2003;8:S500–6.PubMedGoogle Scholar
  73. 73.
    Gibbons GF, Wiggins D, Brown AM, et al. Synthesis and function of hepatic very-low-density lipoprotein. Biochem Soc Trans. 2004;32:59–64.PubMedGoogle Scholar
  74. 74.
    Rustaeus S, Lindberg K, Stillemark P, et al. Assembly of very low density lipoprotein: a two-step process of apolipoprotein B core lipidation. J Nutr. 1999;129:463S–6.PubMedGoogle Scholar
  75. 75.
    Hebbachi AM, Gibbons GF. Microsomal membrane-associated apoB is the direct precursor of secreted VLDL in primary cultures of rat hepatocytes. J Lipid Res. 2001;42:1609–17.PubMedGoogle Scholar
  76. 76.
    Blasiole DA, Davis RA, Attie AD. The physiological and molecular regulation of lipoprotein assembly and secretion. Mol Biosyst. 2007;3:608–19.PubMedGoogle Scholar
  77. 77.
    Reddy JK. Peroxisome proliferators and peroxisome proliferator-activated receptor alpha: biotic and xenobiotic sensing. Am J Pathol. 2004;164:2305–21.PubMedGoogle Scholar
  78. 78.
    Hashimoto T, Fujita T, Usuda N, et al. Peroxisomal and mitochondrial fatty acid beta-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor alpha and peroxisomal fatty acyl-CoA oxidase. Genotype correlation with fatty liver phenotype. J Biol Chem. 1999;274:19228–36.PubMedGoogle Scholar
  79. 79.
    Bartlett K, Eaton S. Mitochondrial beta-oxidation. Eur J Biochem. 2004;271:462–9.PubMedGoogle Scholar
  80. 80.
    Wanders RJ, van Grunsven EG, Jansen GA. Lipid metabolism in peroxisomes: enzymology, functions and dysfunctions of the fatty acid alpha- and beta-oxidation systems in humans. Biochem Soc Trans. 2000;28:141–9.PubMedGoogle Scholar
  81. 81.
    Peluso G, Petillo O, Margarucci S, et al. Differential carnitine/acylcarnitine translocase expression defines distinct metabolic signatures in skeletal muscle cells. J Cell Physiol. 2005;203:439–46.PubMedGoogle Scholar
  82. 82.
    Ramsay RR. The carnitine acyltransferases: modulators of acyl-CoA-dependent reactions. Biochem Soc Trans. 2000;28:182–6.PubMedGoogle Scholar
  83. 83.
    Modre-Osprian R, Osprian I, Tilg B, et al. Dynamic simulations on the mitochondrial fatty acid beta-oxidation network. BMC Syst Biol. 2009;3:1–15.Google Scholar
  84. 84.
    Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15:412–26.PubMedGoogle Scholar
  85. 85.
    Kamijo T, Indo Y, Souri M, et al. Medium chain 3-ketoacyl-coenzyme A thiolase deficiency: a new disorder of mitochondrial fatty acid beta-oxidation. Pediatr Res. 1997;42:569–76.PubMedGoogle Scholar
  86. 86.
    Zhang Z, Zhou Y, Mendelsohn NJ, et al. Regulation of the human long chain acyl-CoA dehydrogenase gene by nuclear hormone receptor transcription factors. Biochim Biophys Acta. 1997;1350:53–64.PubMedGoogle Scholar
  87. 87.
    Rakheja D, Bennett MJ, Rogers BB. Long-chain L-3-hydroxyacyl-coenzyme a dehydrogenase deficiency: a molecular and biochemical review. Lab Invest. 2002;82:815–24.PubMedGoogle Scholar
  88. 88.
    Steinberg SJ, Morgenthaler J, Heinzer AK, et al. Very long-chain acyl-CoA synthetases. Human "bubblegum" represents a new family of proteins capable of activating very long-chain fatty acids. J Biol Chem. 2000;275:35162–9.PubMedGoogle Scholar
  89. 89.
    Baes M, Huyghe S, Carmeliet P, et al. Inactivation of the peroxisomal multifunctional protein-2 in mice impedes the degradation of not only 2-methyl-branched fatty acids and bile acid intermediates but also of very long chain fatty acids. J Biol Chem. 2000;275:16329–36.PubMedGoogle Scholar
  90. 90.
    Pyper S, Reddy JK. PPARα(alpha): energy combustion, hypolipidemia, inflammation and cancer. Nucl Recept Signal. 2010;8:e002.PubMedGoogle Scholar
  91. 91.
    Yu S, Rao S, Reddy JK. Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis. Curr Mol Med. 2003;3:561–72.PubMedGoogle Scholar
  92. 92.
    Reddy JK, Rao MS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol. 2006;290:G852–8.PubMedGoogle Scholar
  93. 93.
    Hunt MC, Alexson SE. Novel functions of acyl-CoA thioesterases and acyltransferases as auxiliary enzymes in peroxisomal lipid metabolism. Prog Lipid Res. 2008;47:405–21.PubMedGoogle Scholar
  94. 94.
    Yeldandi AV, Rao MS, Reddy JK. Hydrogen peroxide generation in peroxisome proliferator-induced oncogenesis. Mutat Res. 2000;448:159–77.PubMedGoogle Scholar
  95. 95.
    Dansen TB, Kops GJ, Denis S, et al. Regulation of sterol carrier protein gene expression by the forkhead transcription factor FOXO3a. J Lipid Res. 2004;45:81–8.PubMedGoogle Scholar
  96. 96.
    Dhar M, Sepkovic DW, Hirani V, et al. Omega oxidation of 3-hydroxy fatty acids by the human CYP4F gene subfamily enzyme CYP4F11. J Lipid Res. 2008;49:612–24.PubMedGoogle Scholar
  97. 97.
    Savas U, Hsu MH, Johnson EF. Differential regulation of human CYP4A genes by peroxisome proliferators and dexamethasone. Arch Biochem Biophys. 2003;409:212–20.PubMedGoogle Scholar
  98. 98.
    Sanders RJ, Ofman R, Duran M, et al. Omega-oxidation of very long-chain fatty acids in human liver microsomes. Implications for X-linked adrenoleukodystrophy. J Biol Chem. 2006;281:13180–7.PubMedGoogle Scholar
  99. 99.
    Mortensen PB. Formation and degradation of dicarboxylic acids in relation to alterations in fatty acid oxidation in rats. Biochim Biophys Acta. 1992;1124:71–9.PubMedGoogle Scholar
  100. 100.
    Wierzbicki AS. Peroxisomal disorders affecting phytanic acid alpha-oxidation: a review. Biochem Soc Trans. 2007;35:881–6.PubMedGoogle Scholar
  101. 101.
    Fukao T, Song XQ, Mitchell GA, et al. Enzymes of ketone body utilization in human tissues: protein and messenger RNA levels of succinyl-coenzyme A (CoA): 3-ketoacid CoA transferase and mitochondrial and cytosolic acetoacetyl-CoA thiolases. Pediatr Res. 1997;42:498–502.PubMedGoogle Scholar
  102. 102.
    Guillou H, Martin PG, Pineau T. Transcriptional regulation of hepatic fatty acid metabolism. Subcell Biochem. 2008;49:3–47.PubMedGoogle Scholar
  103. 103.
    Anderson N, Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol Rev. 2008;60:311–57.PubMedGoogle Scholar
  104. 104.
    Chakravarthy MV, Lodhi IJ, Yin L, et al. Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. Cell. 2009;138:476–88.PubMedGoogle Scholar
  105. 105.
    Kliewer SA, Umesono K, Noonan DJ, et al. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature. 1992;358:771–4.PubMedGoogle Scholar
  106. 106.
    Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347:645–50.PubMedGoogle Scholar
  107. 107.
    Barish GD, Evans RM. PPARs and LXRs: atherosclerosis goes nuclear. Trends Endocrinol Metab. 2004;15:158–65.PubMedGoogle Scholar
  108. 108.
    Liu Z, Sall A, Yang D. MicroRNA: an emerging therapeutic target and intervention tool. Int J Mol Sci. 2008;9:978–99.PubMedGoogle Scholar
  109. 109.
    Eberlé D, Hegarty B, Bossard P, et al. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie. 2004;86:839–48.PubMedGoogle Scholar
  110. 110.
    Dif N, Euthine V, Gonnet E, et al. Insulin activates human sterol-regulatory-element-binding protein-1c (SREBP-1c) promoter through SRE motifs. Biochem J. 2006;400:179–88.PubMedGoogle Scholar
  111. 111.
    Dentin R, Girard J, Postic C. Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie. 2005;87:81–6.PubMedGoogle Scholar
  112. 112.
    Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, et al. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science. 2001;291:2613–6.PubMedGoogle Scholar
  113. 113.
    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;277:19353–7.PubMedGoogle Scholar
  114. 114.
    Denechaud PD, Bossard P, Lobaccaro JM, et al. al; ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver. J Clin Invest. 2008;118:956–64.PubMedGoogle Scholar
  115. 115.
    Postic C, Girard J. The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes Metab. 2008;34:643–8.PubMedGoogle Scholar
  116. 116.
    Bartosch B. Hepatitis C virus and its complex interplay with hepatic glucose and lipid metabolism. J Hepatol. 2009;50:845–7.PubMedGoogle Scholar
  117. 117.
    Denechaud PD, Dentin R, Girard J, et al. Role of ChREBP in hepatic steatosis and insulin resistance. FEBS Lett. 2008;582:68–73.PubMedGoogle Scholar
  118. 118.
    Abu-Elheiga L, Matzuk MM, Kordari P, et al. Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal. Proc Natl Acad Sci U S A. 2005;102:12011–6.PubMedGoogle Scholar
  119. 119.
    Abu-Elheiga L, Oh W, Kordari P, et al. Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. Proc Natl Acad Sci U S A. 2003;100:10207–12.PubMedGoogle Scholar
  120. 120.
    Choi CS, Savage DB, Abu-Elheiga L, et al. Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proc Natl Acad Sci U S A. 2007;104:16480–5.PubMedGoogle Scholar
  121. 121.
    Chakravarthy MV, Pan Z, Zhu Y, et al. "New" hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab. 2005;1:309–22.PubMedGoogle Scholar
  122. 122.
    Sampath H, Ntambi JM. Stearoyl-coenzyme A desaturase 1, sterol regulatory element binding protein-1c and peroxisome proliferator-activated receptor-alpha: independent and interactive roles in the regulation of lipid metabolism. Curr Opin Clin Nutr Metab Care. 2006;9:84–8.PubMedGoogle Scholar
  123. 123.
    Miyazaki M, Flowers MT, Sampath H, et al. Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis. Cell Metab. 2007;6:484–96.PubMedGoogle Scholar
  124. 124.
    McEwan IJ. Nuclear receptors: one big family. Methods Mol Biol. 2009;505:3–18.PubMedGoogle Scholar
  125. 125.
    Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endorcri Rev. 1999;20:649–88.Google Scholar
  126. 126.
    Tontonoz P, Speigelman BM. Fat and beyond: the diverse biology of PPAR gamma. Annu Rev Biochem. 2008;77:289–312.PubMedGoogle Scholar
  127. 127.
    Houten SM, Wanders RJ. A general introduction to the biochemistry of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis. 2010 [Epub ahead of print].Google Scholar
  128. 128.
    Fan CY, Pan J, Usuda N, et al. Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase. Implications for peroxisome proliferator-activated receptor alpha natural ligand metabolism. J Biol Chem. 1998;273:15639–45.PubMedGoogle Scholar
  129. 129.
    Qi C, Zhu Y, Pan J, et al. Absence of spontaneous peroxisome proliferation in enoyl-CoA Hydratase/L-3-hydroxyacyl-CoA dehydrogenase-deficient mouse liver. Further support for the role of fatty acyl CoA oxidase in PPARalpha ligand metabolism. J Biol Chem. 1999;274:15775–80.PubMedGoogle Scholar
  130. 130.
    Lee SS, Pineau T, Drago J, et al. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol. 1995;15:3012–22.PubMedGoogle Scholar
  131. 131.
    Aoyama T, Peters JM, Iritani N, et al. Altered constitutive expression of fatty acid metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor α(alpha)(PPARα(alpha)). J Bil Chem. 1998;273:5678–94.Google Scholar
  132. 132.
    Qi C, Zhu Y, Reddy JK. Peroxisome proliferator-activated receptors, coactivators, and downstream targets. Cell Biochem Biophys. 2000;32:187–204.PubMedGoogle Scholar
  133. 133.
    Nguyen P, Leray V, Diez M, et al. Liver lipid metabolism. J Anim Physiol Anim Nutr (Berl). 2008;92:272–83.Google Scholar
  134. 134.
    Gonzalez FJ, Shah YM. PPARα(alpha): mechanisms of species differences and hepatocarcinogenesis of peroxisome proliferators. Toxicology. 2008;245:2–9.Google Scholar
  135. 135.
    Ip E, Farrell GC, Robertson G, et al. Central role of PPARα(alpha)-dependent hepatic lipid turnover in dietary steatohepatitis in mice. Hepatology. 2003;38:123–32.PubMedGoogle Scholar
  136. 136.
    Sun T, Fu M, Bookout AL, et al. MicroRNA let-7 regulates 3T3-L1 adipogenesis. Mol Endocrinol. 2009;23:925–31.PubMedGoogle Scholar
  137. 137.
    Wilfred BR, Wang WX, Nelson PT. Energizing miRNA research: a review of the role of miRNAs in lipid metabolism, with a prediction that miR-103/107 regulates human metabolic pathways. Mol Genet Metab. 2007;91:209–17.PubMedGoogle Scholar
  138. 138.
    Gatfield D, Le Martelot G, Vejnar CE, et al. Integration of microRNA miR-122 in hepatic circadian gene expression. Genes Dev. 2009;23:1313–26.PubMedGoogle Scholar
  139. 139.
    Nakanishi N, Nakagawa Y, Tokushige N, et al. The up-regulation of microRNA-335 is associated with lipid metabolism in liver and white adipose tissue of genetically obese mice. Biochem Biophys Res Commun. 2009;385:492–6.PubMedGoogle Scholar
  140. 140.
    Jin X, Ye YF, Chen SH, et al. MicroRNA expression pattern in different stages of nonalcoholic fatty liver disease. Dig Liver Dis. 2009;41:289–97.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Jiansheng Huang
  • Jayme Borensztajn
  • Janardan K. Reddy
    • 1
  1. 1.Department of PathologyNorthwestern University, Feinberg School of MedicineChicagoUSA

Personalised recommendations