Functional proteomics of nonalcoholic steatohepatitis: Mitochondrial proteins as targets of S -adenosylmethionine

doi:10.1073/pnas.0536625100

Functional proteomics of nonalcoholic steatohepatitis: Mitochondrial proteins as targets of S-adenosylmethionine

^*Laboratorio de Proteómica, Genómica y Bioinformática, and División de Hepatología y Terapia Génica, Facultad de Medicina, Universidad de Navarra, 31008 Pamplona, Spain; ^†Centro de Estudios e Investigaciones Técnicas de Guipúzcoa, 20008 San Sebastián, Spain; ^‡Servicio de Cirugía, Hospital Príncipe de Asturias, 28802 Alcalá de Henares, Spain; and ^§Division of Gastroenterology and Liver Diseases, University of Southern California Research Center for Liver Diseases, University of Southern California–University of California at Los Angeles Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033

Edited by Rowena G. Matthews, University of Michigan, Ann Arbor, MI, and approved January 9, 2003 (received for review October 31, 2002)

Abstract

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 ≈8 months. Of the 12 proteins, 4 [prohibitin 1 (PHB1), cytochrome c oxidase I and II, and ATPase β-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 ob/ob mice and obese patients who are at risk for nonalcoholic steatohepatitis.

Footnotes

↵ ¶ J.M.M. and F.J.C. contributed equally to this work.
↵ ‖ To whom correspondence should be addressed. E-mail: fjcorrales{at}unav.es.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

AdoMet,

S-adenosylmethionine;

MAT,

methionine adenosyltransferase;

NASH,

nonalcoholic steatohepatitis;

PHB1,

prohibitin 1;

COX,

cytochrome c oxidase;

KO,

knockout;

APA1,

apolipoprotein A1