Abstract
Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in the Western population. By mechanisms that are not completely understood, this disease may progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). db/db mice spontaneously develop hepatic steatosis, which progresses to NASH when these mice are fed a methionine choline-deficient (MCD) diet. The goal of our studies was to identify lipid and methionine metabolism pathways affected by MCD feeding to determine potential causal events leading to the development of NASH from benign steatosis. db/db mice fed the MCD diet for 2 weeks exhibited signs of incipient NASH development such as upregulated cytokines and chemokines. At this time point, MCD diet feeding caused S-adenosylmethionine (SAMe) depletion in db/db mice, while wild-type mice on the same diet retained hepatic SAMe levels. SAMe depletion exerts pleiotropic effects upon liver homeostasis and is commonly associated with a variety of liver insults such as thioacetamide, CCL4, and alcohol treatment; thus, SAMe depletion may serve as the second hit in NASH development. It is possible that differences in hepatic lipid and/or methionine metabolism between wild-type and db/db mice underlay the differential maintenance of SAMe levels during methionine and choline restriction. Indeed, db/db mice exhibited inhibited lipid oxidation pathways, which may be a priming factor for NASH development, and db/db mice fed the MCD diet had differential methionine adenosyltransferase (MAT) expression. The occurrence of SAMe depletion at this early, benign stage of NASH development in db/db mice with fatty liver suggests that SAMe supplementation may be (A) targeted to individuals susceptible to NASH (i.e., NAFLD patients) and (B) preventative of NASH before substantial liver injury has occurred.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Farrell GC, Larter CZ (2006) Nonalcoholic fatty liver disease: From steatosis to cirrhosis. Hepatology 43:S99–S112
Wanless IR, Lentz JS (1990) Fatty liver hepatitis (steatohepatitis) and obesity: An autopsy study with analysis of risk factors. Hepatology 12:1106–1110
Brunt EM (2004) Nonalcoholic steatohepatitis. Semin Liver Dis 24:3–20
Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science 259:87–91
Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632–635
Pascale R, Pirisi L, Daino L, Zanetti S, Satta A, Bartoli E, Feo F (1982) Role of phosphatidylethanolamine methylation in the synthesis of phosphatidylcholine by hepatocytes isolated from choline-deficient rats. FEBS Lett 145:293–297
Sahai A, Malladi P, Pan X, Paul R, Melin-Aldana H, Green RM, Whitington PF (2004) Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: Role of short-form leptin receptors and osteopontin. Am J Physiol Gastrointest Liver Physiol 287:G1035–G1043
Leclercq IA, Farrell GC, Field J, Bell DR, Gonzalez FJ, Robertson GR (2000) Cyp2e1 and cyp4a as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest 105:1067–1075
Oz HS, Chen TS, Neuman M (2007) Methionine deficiency and hepatic injury in a dietary steatohepatitis model. Dig Dis Sci Aug 21 (Epub ahead of print)
Mato JM, Lu SC (2007) Role of s-adenosyl-l-methionine in liver health and injury. Hepatology 45:1306–1312
Oz HS, Im HJ, Chen TS, de Villiers WJ, McClain CJ (2006) Glutathione-enhancing agents protect against steatohepatitis in a dietary model. J Biochem Mol Toxicol 20:39–47
Bray GP, Tredger JM, Williams R (1992) S-adenosylmethionine protects against acetaminophen hepatotoxicity in two mouse models. Hepatology 15:297–301
Garcia-Ruiz C, Morales A, Colell A, Ballesta A, Rodes J, Kaplowitz N, Fernandez-Checa JC (1995) Feeding s-adenosyl-l-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes. Hepatology 21:207–214
Huang ZZ, Mato JM, Kanel G, Lu SC (1999) Differential effect of thioacetamide on hepatic methionine adenosyltransferase expression in the rat. Hepatology 29:1471–1478
Lieber CS, Casini A, DeCarli LM, Kim CI, Lowe N, Sasaki R, Leo MA (1990) S-adenosyl-l-methionine attenuates alcohol-induced liver injury in the baboon. Hepatology 11:165–172
Lu SC, Huang ZZ, Yang H, Mato JM, Avila MA, Tsukamoto H (2000) Changes in methionine adenosyltransferase and s-adenosylmethionine homeostasis in alcoholic rat liver. Am J Physiol Gastrointest Liver Physiol 279:G178–G185
Pascale RM, Marras V, Simile MM, Daino L, Pinna G, Bennati S, Carta M, Seddaiu MA, Massarelli G, Feo F (1992) Chemoprevention of rat liver carcinogenesis by s-adenosyl-l-methionine: a long-term study. Cancer Res 52:4979–4986
Stramentinoli G, Gualano M, Ideo G (1978) Protective role of s-adenosyl-l-methionine on liver injury induced by d-galactosamine in rats. Biochem Pharmacol 27:1431–1433
Varela-Moreiras G, Alonso-Aperte E, Rubio M, Gasso M, Deulofeu R, Alvarez L, Caballeria J, Rodes J, Mato JM (1995) Carbon tetrachloride-induced hepatic injury is associated with global DNA hypomethylation and homocysteinemia: Effect of s-adenosylmethionine treatment. Hepatology 22:1310–1315
Mato JM, Alvarez L, Ortiz P, Pajares MA (1997) S-adenosylmethionine synthesis: molecular mechanisms and clinical implications. Pharmacol Ther 73:265–280
Duce AM, Ortiz P, Cabrero C, Mato JM (1988) S-adenosyl-l-methionine synthetase and phospholipid methyltransferase are inhibited in human cirrhosis. Hepatology 8:65–68
Avila MA, Berasain C, Torres L, Martin-Duce A, Corrales FJ, Yang H, Prieto J, Lu SC, Caballeria J, Rodes J, Mato JM (2000) Reduced mrna abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J Hepatol 33:907–914
Rizki G, Arnaboldi L, Gabrielli B, Yan J, Lee GS, Ng RK, Turner SM, Badger TM, Pitas RE, Maher JJ (2006) Mice fed a lipogenic methionine-choline-deficient diet develop hypermetabolism coincident with hepatic suppression of scd-1. J Lipid Res 47:2280–2290
Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, Bhanot S, Monia BP, Li YX, Diehl AM (2007) Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45:1366–1374
Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226:497–509
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
She QB, Nagao I, Hayakawa T, Tsuge H (1994) A simple hplc method for the determination of s-adenosylmethionine and s-adenosylhomocysteine in rat tissues: the effect of vitamin b6 deficiency on these concentrations in rat liver. Biochem Biophys Res Commun 205:1748–1754
Koteish A, Mae Diehl A (2002) Animal models of steatohepatitis. Best Pract Res Clin Gastroenterol 16:679–690
Finck BN, Kelly DP (2006) Pgc-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest 116:615–622
Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal-Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP (2005) Pgc-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 3:e101
Sonoda J, Mehl IR, Chong LW, Nofsinger RR, Evans RM (2007) Pgc-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc Natl Acad Sci USA 104:5223–5228
Aoyama H, Daitoku H, Fukamizu A (2006) Nutrient control of phosphorylation and translocation of foxo1 in c57bl/6 and db/db mice. Int J Mol Med 18:433–439
Koteish A, Diehl AM (2001) Animal models of steatosis. Semin Liver Dis 21:89–104
Cai J, Sun WM, Hwang JJ, Stain SC, Lu SC (1996) Changes in s-adenosylmethionine synthetase in human liver cancer: Molecular characterization and significance. Hepatology 24:1090–1097
Huang ZZ, Mao Z, Cai J, Lu SC (1998) Changes in methionine adenosyltransferase during liver regeneration in the rat. Am J Physiol 275:G14–G21
Lu SC, Alvarez L, Huang ZZ, Chen L, An W, Corrales FJ, Avila MA, Kanel G, Mato JM (2001) Methionine adenosyltransferase 1a knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation. Proc Natl Acad Sci USA 98:5560–5565
Vendemiale G, Altomare E, Trizio T, Le Grazie C, Di Padova C, Salerno MT, Carrieri V, Albano O (1989) Effects of oral s-adenosyl-l-methionine on hepatic glutathione in patients with liver disease. Scand J Gastroenterol 24:407–415
Mato JM, Camara J, Fernandez de Paz J, Caballeria L, Coll S, Caballero A, Garcia-Buey L, Beltran J, Benita V, Caballeria J, Sola R, Moreno-Otero R, Barrao F, Martin-Duce A, Correa JA, Pares A, Barrao E, Garcia-Magaz I, Puerta JL, Moreno J, Boissard G, Ortiz P, Rodes J (1999) S-adenosylmethionine in alcoholic liver cirrhosis: A randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol 30:1081–1089
Acknowledgements
This study is supported by NIH grants CA53596 and AA14147, and COBRE P20 RR021940 as well as the Molecular Biology Core supported by the COBRE grant.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wortham, M., He, L., Gyamfi, M. et al. The Transition from Fatty Liver to NASH Associates with SAMe Depletion in db/db Mice Fed a Methionine Choline-Deficient Diet. Dig Dis Sci 53, 2761–2774 (2008). https://doi.org/10.1007/s10620-007-0193-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10620-007-0193-7