Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of S-adenosylmethionine.
Recent work shows that S-adenosylmethionine (AdoMet) helps maintain normal liver function as chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. The mechanisms by which these nontraditional functions of AdoMet occur are unknown. Here, we use knockout mice deficient in hepatic AdoMet synthesis (MAT1A(-/-)) to study the proteome of the liver during the development of steatohepatitis. One hundred and seventeen protein spots, differentially expressed during the development of steatohepatitis, were selected and identified by peptide mass fingerprinting. Among them, 12 proteins were found to be affected from birth, when MAT1A(-/-) expression is switched on in WT mouse liver, to the rise of histological lesions, which occurs at approximately 8 months. Of the 12 proteins, 4 [prohibitin 1 (PHB1), cytochrome c oxidase I and II, and ATPase beta-subunit] have known roles in mitochondrial function. We show that the alteration in expression of PHB1 correlates with a loss of mitochondrial function. Experiments in isolated rat hepatocytes indicate that AdoMet regulates PHB1 content, thus suggesting ways by which steatohepatitis may be induced. Importantly, we found the expression of these mitochondrial proteins was abnormal in obob mice and obese patients who are at risk for nonalcoholic steatohepatitis.
Santamaria
Enrique
E
Laboratorio de Proteómica, Genómica y Bioinformática, and División de Hepatologia y Terapia Génica, Facultad de Medicina, Universidad de Navarra, 31008 Pamplona, Spain.
Avila
Matías A
MA
Latasa
M Ujue
MU
Rubio
Angel
A
Martin-Duce
Antonio
A
Lu
Shelly C
SC
Mato
José M
JM
Corrales
Fernando J
FJ
D000818:Animals; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D006505:Hepatitis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008716:Methionine Adenosyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010449:Peptide Mapping; D000091402:Prohibitins; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins; D012436:S-Adenosylmethionine / Q000378:metabolism*
D007527:Isoenzymes; D024101:Mitochondrial Proteins; C000717328:PHB protein, human; D000091402:Prohibitins; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D012436:S-Adenosylmethionine; D003576:Electron Transport Complex IV; D008716:Methionine Adenosyltransferase