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Review Article | Open Access

The molecular pathogenic role of inflammatory stress in dysregulation of lipid homeostasis and hepatic steatosis

Yaxi Chena, Zac Vargheseb, Xiong Z. Ruana,b()
Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China
John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, London, UK

Peer review under responsibility of Chongqing Medical University.

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Abstract

Non-alcoholic Fatty Liver Disease (NAFLD) is becoming the leading cause of chronic liver injury in developed countries and China. Chronic systemic inflammation plays a decisive role and is fundamental in the progression of NAFLD from simple steatosis (SS) toward higher risk nonalcoholic steatohepatitis (NASH) states. However, the exact mechanisms by which inflammation leading to NASH are incompletely understood. In this review, we focus the role of the cross talk between inflammation and lipid homeostasis on the progression of NAFLD.

Keywords

Ectopic lipid depositionInflammationLipid homeostasisLipid redistributionNon-alcoholic fatty liver disease

References

1

Fan JG. Epidemiology of alcoholic and nonalcoholic fatty liver disease in China. Journal of gastroenterology and hepatology. Aug 2013;28(suppl 1):11-17.

Crossref Google Scholar
2

Schattenberg JM, Schuppan D. Nonalcoholic steatohepatitis: the therapeutic challenge of a global epidemic. Curr Opin Lipidol. Dec 2011;22(6):479-488.

Crossref Google Scholar
3

Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. Apr 1998;114(4):842-845.

Crossref Google Scholar
4

Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. Apr 2001;120(5):1183-1192.

Crossref Google Scholar
5

Lalor PF, Faint J, Aarbodem Y, Hubscher SG, Adams DH. The role of cytokines and chemokines in the development of steatohepatitis. Sem Liver Dis. May 2007;27(2):173-193.

Crossref Google Scholar
6

Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology (Baltimore, Md.). Nov 2010;52(5):1836-1846.

Crossref Google Scholar
7

Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci. 2014;15(5):8591-8638.

Crossref Google Scholar
8

Takaki A, Kawai D, Yamamoto K. Molecular mechanisms and new treatment strategies for non-alcoholic steatohepatitis (NASH). Int J Mol Sci. 2014;15(5):7352-7379.

Crossref Google Scholar
9

Haukeland JW, Damas JK, Konopski Z, et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol. Jun 2006;44(6):1167-1174.

Crossref Google Scholar
10

Ford ES. The metabolic syndrome and C-reactive protein, fibrinogen, and leukocyte count: findings from the Third National Health and Nutrition Examination Survey. Atherosclerosis. Jun 2003;168(2):351-358.

Crossref Google Scholar
11

Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology (Baltimore, Md.). Apr 2003;37(4):917-923.

Crossref Google Scholar
12
Tarantino G, Savastano S, Colao A. Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance. World J Gastroenterol. Oct 14 2010;16(38):4773-4783.
Crossref
13

Greenfield JR, Campbell LV. Relationship between inflammation, insulin resistance and type 2 diabetes: 'cause or effect'? Curr Diabetes Rev. May 2006;2(2):195-211.

Crossref Google Scholar
14

Wong VW, Hui AY, Tsang SW, et al. Metabolic and adipokine profile of Chinese patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. Sep 2006;4(9):1154-1161.

Crossref Google Scholar
15

Pinto Lde F, Compri CM, Fornari JV, et al. The immunosuppressant drug, thalidomide, improves hepatic alterations induced by a high-fat diet in mice. Liver Int. Apr 2010;30(4):603-610.

Crossref Google Scholar
16

Koca SS, Bahcecioglu IH, Poyrazoglu OK, Ozercan IH, Sahin K, Ustundag B. The treatment with antibody of TNF-alpha reduces the inflammation, necrosis and fibrosis in the non-alcoholic steatohepatitis induced by methionine- and choline-deficient diet. Inflammation. Apr 2008;31(2):91-98.

Crossref Google Scholar
17

Li Z, Yang S, Lin H, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.). Feb 2003;37(2):343-350.

Crossref Google Scholar
18

Marra F, Bertolani C. Adipokines in liver diseases. Hepatology (Baltimore, Md.). Sep 2009;50(3):957-969.

Crossref Google Scholar
19

El-Assal O, Hong F, Kim WH, Radaeva S, Gao B. IL-6-deficient mice are susceptible to ethanol-induced hepatic steatosis: IL-6 protects against ethanol-induced oxidative stress and mitochondrial permeability transition in the liver. Cell Mol Immunol. Jun 2004;1(3):205-211.

Google Scholar
20

Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. Feb 2005;11(2):183-190.

Crossref Google Scholar
21

Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology (Baltimore, Md.). Aug 2003;38(2):413-419.

Crossref Google Scholar
22

Mas E, Danjoux M, Garcia V, Carpentier S, Segui B, Levade T. IL-6 deficiency attenuates murine diet-induced non-alcoholic steatohepatitis. PloS One. 2009;4(11):e7929.

Crossref Google Scholar
23

Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol. Jun 2008;103(6):1372-1379.

Crossref Google Scholar
24

Sun B, Karin M. Obesity, inflammation, and liver cancer. J Hepatol. Mar 2012;56(3):704-713.

Crossref Google Scholar
25
Chiang SH, Bazuine M, Lumeng CN, et al. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell. Sep 4 2009;138(5):961-975.
Crossref
26

Solinas G, Vilcu C, Neels JG, et al. JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab. Nov 2007;6(5):386-397.

Crossref Google Scholar
27

Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ. Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology (Baltimore, Md.). Jan 2009;49(1):87-96.

Crossref Google Scholar
28

Nakamuta M, Kohjima M, Morizono S, et al. Evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int J Mol Med. Oct 2005;16(4):631-635.

Google Scholar
29

Kohjima M, Enjoji M, Higuchi N, et al. Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int J Mol Med. Sep 2007;20(3):351-358.

Crossref Google Scholar
30

Moylan CA, Pang H, Dellinger A, et al. Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.). Feb 2014;59(2):471-482.

Crossref Google Scholar
31

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. May 2005;115(5):1343-1351.

Crossref Google Scholar
32

Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. Diabetes Metab. Nov 2003;29(5):478-485.

Crossref Google Scholar
33

Rector RS, Thyfault JP, Uptergrove GM, et al. Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J Hepatol. May 2010;52(5):727-736.

Crossref Google Scholar
34
Zhang D, Christianson J, Liu ZX, et al. Resistance to high-fat diet-induced obesity and insulin resistance in mice with very long-chain acyl-CoA dehydrogenase deficiency. Cell Metab. May 5 2010;11(5):402-411.
Crossref
35
Zhang D, Liu ZX, Choi CS, et al. Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Proc Natl Acad Sci USA. Oct 23 2007;104(43):17075-17080.
Crossref
36

Stefanovic-Racic M, Perdomo G, Mantell BS, Sipula IJ, Brown NF, O'Doherty RM. A moderate increase in carnitine palmitoyltransferase 1a activity is sufficient to substantially reduce hepatic triglyceride levels. Am J Physiol. May 2008;294(5):E969-E977.

Crossref Google Scholar
37

Savage DB, Choi CS, Samuel VT, 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 Investig. Mar 2006;116(3):817-824.

Crossref Google Scholar
38

Frederico MJ, Vitto MF, Cesconetto PA, et al. Short-term inhibition of SREBP-1c expression reverses diet-induced non-alcoholic fatty liver disease in mice. Scand J Gastroenterol. Nov 2011;46(11):1381-1388.

Crossref Google Scholar
39

Knebel B, Haas J, Hartwig S, et al. Liver-specific expression of transcriptionally active SREBP-1c is associated with fatty liver and increased visceral fat mass. PloS One. 2012;7(2):e31812.

Crossref Google Scholar
40
Kao HJ, Cheng CF, Chen YH, et al. ENU mutagenesis identifies mice with cardiac fibrosis and hepatic steatosis caused by a mutation in the mitochondrial trifunctional protein beta-subunit. Human Mole Genet. Dec 15 2006;15(24):3569-3577.
Crossref
41
Le Borgne F, Ben Mohamed A, Logerot M, Garnier E, Demarquoy J. Changes in carnitine octanoyltransferase activity induce alteration in fatty acid metabolism. Biochem Biophysical Res Commun. Jun 17 2011;409(4):699-704.
Crossref
42

Ma KL, Ruan XZ, Powis SH, Chen Y, Moorhead JF, Varghese Z. Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice. Diabetes Metab. Sep 2008;48(3):770-781.

Crossref Google Scholar
43

Wal JM. Cow's milk proteins/allergens. Annals of allergy, asthma & immunology : official publication of the American College of Allergy. Asthma Immunol. Dec 2002;89(6 suppl 1):3-10.

Crossref Google Scholar
44

Miura K, Takahashi Y, Shirasawa H. Immunohistochemical detection of serum amyloid A protein in the liver and the kidney after casein injection. Lab Invest. Oct 1985;53(4):453-463.

Google Scholar
45
Zhang H, Ching S, Chen Q, Li Q, An Y, Quan N. Localized inflammation in peripheral tissue signals the CNS for sickness response in the absence of interleukin-1 and cyclooxygenase-2 in the blood and brain. Neuroscience. Dec 10 2008;157(4):895-907.
Crossref
46

Caballero F, Fernandez A, De Lacy AM, Fernandez-Checa JC, Caballeria J, Garcia-Ruiz C. Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH. J Hepatol. Apr 2009;50(4):789-796.

Crossref Google Scholar
47

Mari M, Caballero F, Colell A, et al. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab. Sep 2006;4(3):185-198.

Crossref Google Scholar
48

Zhao L, Chen Y, Tang R, et al. Inflammatory stress exacerbates hepatic cholesterol accumulation via increasing cholesterol uptake and de novo synthesis. J Gastroenterol Hepatol. May 2011;26(5):875-883.

Crossref Google Scholar
49

Chen Y, Chen Y, Zhao L, et al. Inflammatory stress exacerbates hepatic cholesterol accumulation via disrupting cellular cholesterol export. J Gastroenterol Hepatol. May 2012;27(5):974-984.

Crossref Google Scholar
50
Zhang W, Kudo H, Kawai K, et al. Tumor necrosis factor-alpha accelerates apoptosis of steatotic hepatocytes from a murine model of non-alcoholic fatty liver disease. Biochem Biophys Res Commun. Jan 22 2010;391(4):1731-1736.
Crossref
51

Senokuchi T, Liang CP, Seimon TA, et al. Forkhead transcription factors (FoxOs) promote apoptosis of insulin-resistant macrophages during cholesterol-induced endoplasmic reticulum stress. Diabetes. Nov 2008;57(11):2967-2976.

Crossref Google Scholar
52

Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.). Jul 2006;44(1):27-33.

Crossref Google Scholar
53

Chen CH, Huang MH, Yang JC, et al. Prevalence and risk factors of nonalcoholic fatty liver disease in an adult population of Taiwan: metabolic significance of nonalcoholic fatty liver disease in nonobese adults. J Clin Gastroenterol. Sep 2006;40(8):745-752.

Crossref Google Scholar
54
Wong RJ, Ahmed A. Obesity and non-alcoholic fatty liver disease: disparate associations among Asian populations. World J Hepatol. May 27 2014;6(5):263-273.
Crossref
55

Manco M, Calvani M, Mingrone G. Effects of dietary fatty acids on insulin sensitivity and secretion. Diabetes Obes Metab. Nov 2004;6(6):402-413.

Crossref Google Scholar
56
Yu YH, Ginsberg HN. Adipocyte signaling and lipid homeostasis: sequelae of insulin-resistant adipose tissue. Circ Res. May 27 2005;96(10):1042-1052.
Crossref
57

Asrih M, Jornayvaz FR. Inflammation as a potential link between nonalcoholic fatty liver disease and insulin resistance. J Endocrinol. Sep 2013;218(3):R25-R36.

Crossref Google Scholar
58

Mei M, Zhao L, Li Q, et al. Inflammatory stress exacerbates ectopic lipid deposition in C57BL/6J mice. Lipids Health Dis. 2011;10:110.

Crossref Google Scholar
59
Bezaire V, Mairal A, Anesia R, Lefort C, Langin D. Chronic TNFalpha and cAMP pre-treatment of human adipocytes alter HSL, ATGL and perilipin to regulate basal and stimulated lipolysis. FEBS Lett. Sep 17 2009;583(18):3045-3049.
Crossref
60

Laurencikiene J, van Harmelen V, Arvidsson Nordstrom E, et al. NF-kappaB is important for TNF-alpha-induced lipolysis in human adipocytes. J Lipid Res. May 2007;48(5):1069-1077.

Crossref Google Scholar
61

Ranjit S, Boutet E, Gandhi P, et al. Regulation of fat specific protein 27 by isoproterenol and TNF-alpha to control lipolysis in murine adipocytes. J Lipid Res. Feb 2011;52(2):221-236.

Crossref Google Scholar
62
Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. Mar 2 2012;148(5):852-871.
Crossref
63
Kim JK, Fillmore JJ, Chen Y, et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA. Jun 19 2001;98(13):7522-7527.
Crossref
64
Merkel M, Weinstock PH, Chajek-Shaul T, et al. Lipoprotein lipase expression exclusively in liver. A mouse model for metabolism in the neonatal period and during cachexia. J Clin Invest. Sep 1 1998;102(5):893-901.
Crossref
65

Falcon A, Doege H, Fluitt A, et al. FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase. Am J Physiol Endocrinol Metab. Sep 2010;299(3):E384-E393.

Crossref Google Scholar
66
Doege H, Grimm D, Falcon A, 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. Aug 8 2008;283(32):22186-22192.
Crossref
67
Kennedy DJ, Kuchibhotla S, Westfall KM, Silverstein RL, Morton RE, Febbraio M. A CD36-dependent pathway enhances macrophage and adipose tissue inflammation and impairs insulin signalling. Cardiovasc Res. Feb 15 2011;89(3):604-613.
Crossref
68

Lauzier B, Merlen C, Vaillant F, et al. Post-translational modifications, a key process in CD36 function: lessons from the spontaneously hypertensive rat heart. J Mol Cell Cardiol. Jul 2011;51(1):99-108.

Crossref Google Scholar
69

Greco D, Kotronen A, Westerbacka J, et al. Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol. May 2008;294(5):G1281-G1287.

Crossref Google Scholar
70

Krammer J, Digel M, Ehehalt F, Stremmel W, Fullekrug J, Ehehalt R. Overexpression of CD36 and acyl-CoA synthetases FATP2, FATP4 and ACSL1 increases fatty acid uptake in human hepatoma cells. Int J Med Sci. 2011;8(7):599-614.

Crossref Google Scholar
71

Koonen DP, Jacobs RL, Febbraio M, et al. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes. Dec 2007;56(12):2863-2871.

Crossref Google Scholar
72

Miquilena-Colina ME, Lima-Cabello E, Sanchez-Campos S, 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. Oct 2011;60(10):1394-1402.

Crossref Google Scholar
Genes & Diseases
Volume 1 Issue 1,
September 2014
Pages 106-112
DOI: 10.1016/j.gendis.2014.07.007
Cite this article:
Chen Y, Varghese Z, Ruan XZ. The molecular pathogenic role of inflammatory stress in dysregulation of lipid homeostasis and hepatic steatosis. Genes & Diseases, 2014, 1(1): 106-112. https://doi.org/10.1016/j.gendis.2014.07.007
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