Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-L-methionine and glutathione.
The pathogenesis and treatment of nonalcoholic steatohepatitis (NASH) are not well established. Feeding a diet deficient in both methionine and choline (MCD) is one of the most common models of NASH, which is characterized by steatosis, mitochondrial dysfunction, hepatocellular injury, oxidative stress, inflammation, and fibrosis. However, the individual contribution of the lack of methionine and choline in liver steatosis, advanced pathology and impact on mitochondrial S-adenosyl-L-methionine (SAM) and glutathione (GSH), known regulators of disease progression, has not been specifically addressed. Here, we examined the regulation of mitochondrial SAM and GSH and signs of disease in mice fed a MCD, methionine-deficient (MD), or choline-deficient (CD) diet. The MD diet reproduced most of the deleterious effects of MCD feeding, including weight loss, hepatocellular injury, oxidative stress, inflammation, and fibrosis, whereas CD feeding was mainly responsible for steatosis, characterized by triglycerides and free fatty acids accumulation. These findings were preceded by MCD- or MD-mediated SAM and GSH depletion in mitochondria due to decreased mitochondrial membrane fluidity associated with a lower phosphatidylcholine/phosphatidylethanolamine ratio. MCD and MD but not CD feeding resulted in increased ceramide levels by acid sphingomyelinase. Moreover, GSH ethyl ester or SAM therapy restored mitochondrial GSH and ameliorated hepatocellular injury in mice fed a MCD or MD diet. Thus, the depletion of SAM and GSH in mitochondria is an early event in the MCD model of NASH, which is determined by the lack of methionine. Moreover, therapy using permeable GSH prodrugs may be of relevance in NASH.
Caballero
Francisco
F
Liver Unit, Centro de Investigaciones Biomédicas Esther Koplowitz, Instituto Malalties Digestivas i Metaboliques, Hospital Clínic i Provincial, 08036 Barcelona, Spain.
Fernández
Anna
A
Matías
Nuria
N
Martínez
Laura
L
Fucho
Raquel
R
Elena
Montserrat
M
Caballeria
Joan
J
Morales
Albert
A
Fernández-Checa
José C
JC
García-Ruiz
Carmen
C
D000821:Animal Feed; D000818:Animals; D002518:Ceramides / Q000737:chemistry; D002794:Choline / Q000737:chemistry*; D005234:Fatty Liver / Q000378:metabolism*; D005978:Glutathione / Q000737:chemistry*; D007249:Inflammation; D008055:Lipids / Q000737:chemistry; D008297:Male; D008715:Methionine / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry; D012436:S-Adenosylmethionine / Q000737:chemistry*; D013108:Sphingomyelin Phosphodiesterase / Q000737:chemistry
D002518:Ceramides; D008055:Lipids; D011355:Prodrugs; D012436:S-Adenosylmethionine; D008715:Methionine; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D005978:Glutathione; D002794:Choline
Free Radic Biol Med. 2010 Jan 15;48(2):357-71
19914374
Gastroenterology. 2001 Apr;120(5):1183-92
11266382
J Hepatol. 2009 Jul;51(1):176-86
19450891
Semin Liver Dis. 2004 Feb;24(1):3-20
15085483
Antioxid Redox Signal. 2009 Nov;11(11):2685-700
19558212
J Nutr. 2008 Oct;138(10):1872-9
18806095
Anal Biochem. 1988 Jun;171(2):373-81
3407935
Hepatology. 2008 Aug;48(2):458-73
18666257
Alcohol Clin Exp Res. 2009 Jul;33(7):1169-80
19389197
J Neurosci. 2009 May 20;29(20):6394-405
19458211
Am J Pathol. 2010 Feb;176(2):744-53
20019186
J Gastroenterol Hepatol. 2007 Sep;22(9):1526-33
17716355
Cell Metab. 2006 May;3(5):321-31
16679290
N Engl J Med. 2002 Apr 18;346(16):1221-31
11961152
Antioxid Redox Signal. 2010 Jun 1;12(11):1295-331
19803748
Mol Pharmacol. 2003 Aug;64(2):502-11
12869656
Gastroenterology. 1998 Apr;114(4):842-5
9547102
PLoS One. 2009 Nov 20;4(11):e7929
19936233
Nature. 1997 Oct 9;389(6651):610-4
9335502
J Biol Chem. 1956 Sep;222(1):185-91
13366992
J Biol Chem. 2004 Jun 4;279(23):23916-24
15024002
J Hepatol. 2009 Apr;50(4):789-96
19231010
J Biol Chem. 2003 Sep 5;278(36):33928-35
12821666
World J Gastroenterol. 2004 Jun 15;10(12):1699-708
15188490
Dig Dis Sci. 2008 Mar;53(3):767-76
17710550
Hepatology. 2009 Nov;50(5):1421-30
19676126
J Nutr. 2002 Jul;132(7):1840-7
12097657
N Engl J Med. 2000 Nov 16;343(20):1467-76
11078773
J Biochem Mol Toxicol. 2006;20(1):39-47
16498637
Hepatology. 2000 Jul;32(1):56-65
10869289
Antioxid Redox Signal. 2009 Oct;11(10):2573-84
19764881
Hepatology. 2001 Dec;34(6):1158-63
11732005
Nutrition. 2010 Nov-Dec;26(11-12):1170-5
20036517
J Biol Chem. 2009 Nov 13;284(46):31807-16
19762918
Hepatology. 2006 Sep;44(3):561-72
16941686
Hepatology. 1995 Jan;21(1):207-14
7806156
Cell Metab. 2006 Sep;4(3):185-98
16950136
Int J Biochem Cell Biol. 2009 May;41(5):969-76
19027869
J Mol Med (Berl). 2009 Jul;87(7):679-95
19352614
Gut. 2008 Jul;57(7):957-65
18308829
J Lipid Res. 2008 Jun;49(6):1187-94
18204095
Hepatology. 2007 May;45(5):1306-12
17464973