Nutrition and Nonalcoholic Fatty Liver Disease: The Significance of Cholesterol
This article is part of Special Issue:
Munechika Enjoji,
Kenichiro Yasutake,
Motoyuki Kohjima,
Makoto Nakamuta,
Corresponding Author
Munechika Enjoji
Health Care Center, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan fukuoka-u.ac.jp
Clinical Research Center, Kyushu Medical Center, National Hospital Organization, Fukuoka 810-8563, Japan
Search for more papers by this authorKenichiro Yasutake
Clinical Research Center, Kyushu Medical Center, National Hospital Organization, Fukuoka 810-8563, Japan
Search for more papers by this authorMotoyuki Kohjima
Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka 810-8563, Japan
Search for more papers by this authorMakoto Nakamuta
Clinical Research Center, Kyushu Medical Center, National Hospital Organization, Fukuoka 810-8563, Japan
Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka 810-8563, Japan
Search for more papers by this authorMunechika Enjoji,
Kenichiro Yasutake,
Motoyuki Kohjima,
Makoto Nakamuta,
Corresponding Author
Munechika Enjoji
Health Care Center, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan fukuoka-u.ac.jp
Clinical Research Center, Kyushu Medical Center, National Hospital Organization, Fukuoka 810-8563, Japan
Search for more papers by this authorKenichiro Yasutake
Clinical Research Center, Kyushu Medical Center, National Hospital Organization, Fukuoka 810-8563, Japan
Search for more papers by this authorMotoyuki Kohjima
Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka 810-8563, Japan
Search for more papers by this authorMakoto Nakamuta
Clinical Research Center, Kyushu Medical Center, National Hospital Organization, Fukuoka 810-8563, Japan
Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka 810-8563, Japan
Search for more papers by this authorAcademic Editor: Manuela Neuman
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that ranges in severity from simple steatosis to cirrhosis. NAFLD is considered to be associated with hepatic metabolic disorders, resulting in overaccumulation of fatty acids/triglycerides and cholesterol. The pathogenesis and progression of NAFLD are generally explained by the “two-hit theory.” Most studies of lipid metabolism in the NAFLD liver have focused on the metabolism of fatty acids/triglycerides; therefore, the impact of cholesterol metabolism is still ambiguous. In this paper, we review recent studies on NAFLD from the viewpoint of hepatic lipid metabolism-associated factors and discuss the impact of disordered cholesterol metabolism in the etiology of NAFLD. The clinical significance of managing cholesterol metabolism, an option for the treatment of NAFLD, is also discussed.
References
- 1 Brunt E. M. and Tiniakos D. G., Histopathology of nonalcoholic fatty liver disease, World Journal of Gastroenterology. (2010) 16, no. 42, 5286–5296, 2-s2.0-78649433367, https://doi.org/10.3748/wjg.v16.i42.5286.
- 2 Schaffner F. and Thaler H. H., Nonalcoholic fatty liver disease, Progress in Liver Diseases. (1986) 8, 283–298, 2-s2.0-0022568321.
- 3 Hashimoto E., Taniai M., Kaneda H., Tokushige K., Hasegawa K., Okuda H., Shiratori K., and Takasaki K., Comparison of hepatocellular carcinoma patients with alcoholic liver disease and nonalcoholic steatohepatitis, Alcoholism: Clinical and Experimental Research. (2004) 28, no. 8, supplement 2, S164–S168, 2-s2.0-16644399074, https://doi.org/10.1097/01.ALC.0000133547.70803.83.
- 4 Hashimoto E., Yatsuji S., Tobari M., Taniai M., Torii N., Tokushige K., and Shiratori K., Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis, Journal of Gastroenterology. (2009) 44, no. 19, 89–95, 2-s2.0-58849090967, https://doi.org/10.1007/s00535-008-2262-x.
- 5 Yatsuji S., Hashimoto E., Tobari M., Taniai M., Tokushige K., and Shiratori K., Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C, Journal of Gastroenterology and Hepatology. (2009) 24, no. 2, 248–254, 2-s2.0-58849132440, https://doi.org/10.1111/j.1440-1746.2008.05640.x.
- 6 Angulo P., Medical progress: nonalcoholic fatty liver disease, The New England Journal of Medicine. (2002) 346, no. 16, 1221–1231, 2-s2.0-0037129380, https://doi.org/10.1056/NEJMra011775.
- 7 James O. F. and Day C. P., Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance, Journal of Hepatology. (1998) 29, no. 3, 495–501, 2-s2.0-0032171686, https://doi.org/10.1016/S0168-8278(98)80073-1.
- 8 You M., Matsumoto M., Pacold C. M., Cho W. K., and Crabb D. W., The role of AMP-activated protein kinase in the action of ethanol in the liver, Gastroenterology. (2004) 127, no. 6, 1798–1808, 2-s2.0-9644290860, https://doi.org/10.1053/j.gastro.2004.09.049.
- 9 Xie Z., Li H., Wang K., Lin J., Wang Q., Zhao G., Jia W., and Zhang Q., Analysis of transcriptome and metabolome profiles alterations in fatty liver induced by high-fat diet in rat, Metabolism. (2010) 59, no. 4, 554–560, 2-s2.0-77949444189, https://doi.org/10.1016/j.metabol.2009.08.022.
- 10 Enjoji M., Yada R., Fujino T., Yoshimoto T., Yada M., Harada N., Higuchi N., Kato M., Kohjima M., Taketomi A., Maehara Y., Nakashima M., Kotoh K., and Nakamuta M., The state of cholesterol metabolism in the liver of patients with primary biliary cirrhosis: the role of MDR3 expression, Hepatology International. (2009) 3, no. 2, 490–496, 2-s2.0-68949148804, https://doi.org/10.1007/s12072-009-9137-y.
- 11 Higuchi N., Kato M., Shundo Y., Tajiri H., Tanaka M., Yamashita N., Kohjima M., Kotoh K., Nakamuta M., Takayanagi R., and Enjoji M., Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease, Hepatology Research. (2008) 38, no. 11, 1122–1129, 2-s2.0-53349153430, https://doi.org/10.1111/j.1872-034X.2008.00382.x.
- 12 Kohjima M., Enjoji M., Higuchi N., Kato M., Kotoh K., Yoshimoto T., Fujino T., Yada M., Yada R., Harada N., Takayanagi R., and Nakamuta M., Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease, International Journal of Molecular Medicine. (2007) 20, no. 3, 351–358, 2-s2.0-35148881190.
- 13 Nakamuta M., Kohjima M., Higuchi N., Kato M., Kotoh K., Yoshimoto T., Yada M., Yada R., Takemoto R., Fukuizumi K., Harada N., Taketomi A., Maehara Y., Nakashima M., and Enjoji M., The significance of differences in fatty acid metabolism between obese and non-obese patients with non-alcoholic fatty liver disease, International Journal of Molecular Medicine. (2008) 22, no. 5, 663–667, 2-s2.0-59149104628, https://doi.org/10.3892/ijmm_00000070.
- 14 Nakamuta M., Kohjima M., Morizono S., Kotoh K., Yoshimoto T., Miyagi I., and Enjoji M., Evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease, International Journal of Molecular Medicine. (2005) 16, no. 4, 631–635, 2-s2.0-29244465372.
- 15 Browning J. D. and Horton J. D., Molecular mediators of hepatic steatosis and liver injury, Journal of Clinical Investigation. (2004) 114, no. 2, 147–152, 2-s2.0-4043077961, https://doi.org/10.1172/JCI200422422.
- 16 Cheung O. and Sanyal A. J., Recent advances in nonalcoholic fatty liver disease, Current Opinion in Gastroenterology. (2009) 25, no. 3, 230–237, 2-s2.0-67651099223, https://doi.org/10.1097/MOG.0b013e3283294a18.
- 17 Chalasani N., Gorski J. C., Asghar M. S., Asghar A., Foresman B., Hall S. D., and Crabb D. W., Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis, Hepatology. (2003) 37, no. 3, 544–550, 2-s2.0-0037369729, https://doi.org/10.1053/jhep.2003.50095.
- 18 Kotronen A., Seppälä-Lindroos A., Vehkavaara S., Bergholm R., Frayn K. N., Fielding B. A., and Yki-Järvinen H., Liver fat and lipid oxidation in humans, Liver International. (2009) 29, no. 9, 1439–1446, 2-s2.0-70449698539, https://doi.org/10.1111/j.1478-3231.2009.02076.x.
- 19 Bugianesi E., Gastaldelli A., Vanni E., Gambino R., Cassader M., Baldi S., Ponti V., Pagano G., Ferrannini E., and Rizzetto M., Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms, Diabetologia. (2005) 48, no. 4, 634–642, 2-s2.0-20944450486, https://doi.org/10.1007/s00125-005-1682-x.
- 20 Savage D. B. and Semple R. K., Recent insights into fatty liver, metabolic dyslipidaemia and their links to insulin resistance, Current Opinion in Lipidology. (2010) 21, no. 4, 329–336, 2-s2.0-77954956697, https://doi.org/10.1097/MOL.0b013e32833b7782.
- 21 Chen G., Liang G., Ou J., Goldstein J. L., and Brown M. S., Central role for liver X receptor in insulin-mediated activation of SREBP-1c transcription and stimulation of fatty acid synthesis in liver, Proceedings of the National Academy of Sciences of the United States of America. (2004) 101, no. 31, 11245–11250, 2-s2.0-3843061127, https://doi.org/10.1073/pnas.0404297101.
- 22 Osei-Hyiaman D., DePetrillo M., Pacher P., Liu J., Radaeva S., Bátkai S., Harvey-White J., Mackie K., Offertáler L., Wang L., and Kunos G., Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity, Journal of Clinical Investigation. (2005) 115, no. 5, 1298–1305, 2-s2.0-20944436157, https://doi.org/10.1172/JCI200523057.
- 23 Jeong W. I., Osei-Hyiaman D., Park O., Liu J., Bátkai S., Mukhopadhyay P., Horiguchi N., Harvey-White J., Marsicano G., Lutz B., Gao B., and Kunos G., Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver, Cell Metabolism. (2008) 7, no. 3, 227–235, 2-s2.0-38649114788, https://doi.org/10.1016/j.cmet.2007.12.007.
- 24 Purohit V., Rapaka R., and Shurtleff D., Role of cannabinoids in the development of fatty liver (steatosis), The AAPS Journal. (2010) 12, no. 2, 233–237, 2-s2.0-77950681221, https://doi.org/10.1208/s12248-010-9178-0.
- 25 Grundy S. M. and Metzger A. L., A physiological method for estimation of hepatic secretion of biliary lipids in man, Gastroenterology. (1972) 62, no. 6, 1200–1217, 2-s2.0-0015359158.
- 26 Altmann S. W., Davis H. R., Zhu L. J., Yao X., Hoos L. M., Tetzloff G., Iyer S. P. N., Maguire M., Golovko A., Zeng M., Wang L., Murgolo N., and Graziano M. P., Niemann-pick C1 Like 1 protein is critical for intestinal cholesterol absorption, Science. (2004) 303, no. 5661, 1201–1204, 2-s2.0-10744221008, https://doi.org/10.1126/science.1093131.
- 27 Graf G. A., Li W. P., Gerard R. D., Gelissen I., White A., Cohen J. C., and Hobbs H. H., Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface, Journal of Clinical Investigation. (2002) 110, no. 5, 659–669, 2-s2.0-0036731990, https://doi.org/10.1172/JCI200216000.
- 28 Goldstein J. L., DeBose-Boyd R. A., and Brown M. S., Protein sensors for membrane sterols, Cell. (2006) 124, no. 1, 35–46, 2-s2.0-30344473341, https://doi.org/10.1016/j.cell.2005.12.022.
- 29 Donohue T. M., Alcohol-induced steatosis in liver cells, World Journal of Gastroenterology. (2007) 13, no. 37, 4974–4978, 2-s2.0-34848817401.
- 30 Nakamuta M., Fujino T., Yada R., Yada M., Yasutake K., Yoshimoto T., Harada N., Higuchi N., Kato M., Kohjima M., Taketomi A., Maehara Y., Nakashima M., Kotoh K., and Enjoji M., Impact of cholesterol metabolism and the LXRα-SREBP-1c pathway on nonalcoholic fatty liver disease, International Journal of Molecular Medicine. (2009) 23, no. 5, 603–608, 2-s2.0-67649429268, https://doi.org/10.3892/ijmm_00000170.
- 31 Sugimoto T., Yamashita S., Ishigami M., Sakai N., Hirano K. I., Tahara M., Matsumoto K., Nakamura T., and Matsuzawa Y., Decreased microsomal triglyceride transfer protein activity contributes to initiation of alcoholic liver steatosis in rats, Journal of Hepatology. (2002) 36, no. 2, 157–162, 2-s2.0-0036169936, https://doi.org/10.1016/S0168-8278(01)00263-X.
- 32 Zelcer N. and Tontonoz P., Liver X receptors as integrators of metabolic and inflammatory signaling, Journal of Clinical Investigation. (2006) 116, no. 3, 607–614, 2-s2.0-33644651160, https://doi.org/10.1172/JCI27883.
- 33 Musso G., Gambino R., De Michieli F., Cassader M., Rizzetto M., Durazzo M., Fagà E., Silli B., and Pagano G., Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis, Hepatology. (2003) 37, no. 4, 909–916, 2-s2.0-0037382071, https://doi.org/10.1053/jhep.2003.50132.
- 34 Solga S., Alkhuraishe A. R., Clark J. M., Torbenson M., Greenwald A., Diehl A. M., and Magnuson T., Dietary composition and nonalcoholic fatty liver disease, Digestive Diseases and Sciences. (2004) 49, no. 10, 1578–1583, 2-s2.0-5044234968, https://doi.org/10.1023/B:DDAS.0000043367.69470.b7.
- 35 Toshimitsu K., Matsuura B., Ohkubo I., Niiya T., Furukawa S., Hiasa Y., Kawamura M., Ebihara K., and Onji M., Dietary habits and nutrient intake in non-alcoholic steatohepatitis, Nutrition. (2007) 23, no. 1, 46–52, 2-s2.0-33845632821, https://doi.org/10.1016/j.nut.2006.09.004.
- 36 Thuy S., Ladurner R., Volynets V., Wagner S., Strahl S., Königsrainer A., Maier K. P., Bischoff S. C., and Bergheim I., Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake, The Journal of Nutrition. (2008) 138, no. 8, 1452–1455, 2-s2.0-49449083979.
- 37 Yasutake K., Nakamuta M., Shima Y., Ohyama A., Masuda K., Haruta N., Fujino T., Aoyagi Y., Fukuizumi K., Yoshimoto T., Takemoto R., Miyahara T., Harada N., Hayata F., Nakashima M., and Enjoji M., Nutritional investigation of non-obese patients with non-alcoholic fatty liver disease: the significance of dietary cholesterol, Scandinavian Journal of Gastroenterology. (2009) 44, no. 4, 471–477, 2-s2.0-67049114700, https://doi.org/10.1080/00365520802588133.
- 38 Kainuma M., Fujimoto M., Sekiya N., Tsuneyama K., Cheng C., Takano Y., Terasawa K., and Shimada Y., Cholesterol-fed rabbit as a unique model of nonalcoholic, nonobese, non-insulin-resistant fatty liver disease with characteristic fibrosis, Journal of Gastroenterology. (2006) 41, no. 10, 971–980, 2-s2.0-33750996121, https://doi.org/10.1007/s00535-006-1883-1.
- 39 Matsuzawa N., Takamura T., Kurita S., Misu H., Ota T., Ando H., Yokoyama M., Honda M., Zen Y., Nakanuma Y., Miyamoto K. I., and Kaneko S., Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet, Hepatology. (2007) 46, no. 5, 1392–1403, 2-s2.0-36348935003, https://doi.org/10.1002/hep.21874.
- 40 Wouters K., van Gorp P. J., Bieghs V., Gijbels M. J., Duimel H., Lütjohann D., Kerksiek A., van Kruchten R., Maeda N., Staels B., van Bilsen M., Shiri-Sverdlov R., and Hofker M. H., Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis, Hepatology. (2008) 48, no. 2, 474–486, 2-s2.0-49649110937, https://doi.org/10.1002/hep.22363.
- 41 Fernández A., Colell A., Garcia-Ruiz C., and Fernandez-Checa J. C., Cholesterol and sphingolipids in alcohol-induced liver injury, Journal of Gastroenterology and Hepatology. (2008) 23, no. 1, supplement 1, S9–S15, 2-s2.0-40749083610, https://doi.org/10.1111/j.1440-1746.2007.05280.x.
- 42 Yamaguchi K., Yang L., McCall S., Huang J., Xing X. Y., Pandey S. K., Bhanot S., Monia B. P., Li Y. X., and Diehl A. M., Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis, Hepatology. (2007) 45, no. 6, 1366–1374, 2-s2.0-34250356015, https://doi.org/10.1002/hep.21655.
- 43 Sudhop T., Lütjohann D., Kodal A., Igel M., Tribble D. L., Shah S., Perevozskaya I., and Von Bergmann K., Inhibition of intestinal cholesterol absorption by ezetimibe in humans, Circulation. (2002) 106, no. 15, 1943–1948, 2-s2.0-0037044454, https://doi.org/10.1161/01.CIR.0000034044.95911.DC.
- 44 Turley S. D. and Dietschy J. M., Sterol absorption by the small intestine, Current Opinion in Lipidology. (2003) 14, no. 3, 233–240, 2-s2.0-0038509061, https://doi.org/10.1097/00041433-200306000-00002.
- 45 Enjoji M., Machida K., Kohjima M., Kato M., Kotoh K., Matsunaga K., Nakashima M., and Nakamuta M., NPC1L1 inhibitor ezetimibe is a reliable therapeutic agent for non-obese patients with nonalcoholic fatty liver disease, Lipids in Health and Disease. (2010) 9, article 29, https://doi.org/10.1186/1476-511X-9-29.
- 46 Davies J. P., Scott C., Oishi K., Liapis A., and Ioannou Y. A., Inactivation of NPC1L1 causes multiple lipid transport defects and protects against diet-induced hypercholesterolemia, Journal of Biological Chemistry. (2005) 280, no. 13, 12710–12720, 2-s2.0-16844376244, https://doi.org/10.1074/jbc.M409110200.
- 47 Deushi M., Nomura M., Kawakami A., Haraguchi M., Ito M., Okazaki M., Ishii H., and Yoshida M., Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome, FEBS Letters. (2007) 581, no. 29, 5664–5670, 2-s2.0-36549013633, https://doi.org/10.1016/j.febslet.2007.11.023.
- 48 Hyogo H., Tazuma S., Arihiro K., Iwamoto K., Nabeshima Y., Inoue M., Ishitobi T., Nonaka M., and Chayama K., Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia, Metabolism. (2008) 57, no. 12, 1711–1718, 2-s2.0-55649083505, https://doi.org/10.1016/j.metabol.2008.07.030.
- 49 Kashi M. R., Torres D. M., and Harrison S. A., Current and emerging therapies in nonalcoholic fatty liver disease, Seminars in Liver Disease. (2008) 28, no. 4, 396–406, 2-s2.0-56649117397, https://doi.org/10.1055/s-0028-1091984.
- 50 Nelson A., Torres D. M., Morgan A. E., Fincke C., and Harrison S. A., A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial, Journal of Clinical Gastroenterology. (2009) 43, no. 10, 990–994, 2-s2.0-74949102941, https://doi.org/10.1097/MCG.0b013e31819c392e.
- 51 Enjoji M. and Nakamuta M., Is the control of dietary cholesterol intake sufficiently effective to ameliorate nonalcoholic fatty liver disease?, World Journal of Gastroenterology. (2010) 16, no. 7, 800–803, 2-s2.0-77449157160, https://doi.org/10.3748/wjg.v16.i7.800.
