The transition from fatty liver to NASH associates with SAMe depletion in db/db mice fed a methionine choline-deficient diet

Matthew Wortham, Lin He, Maxwell Gyamfi, Bryan L. Copple, Yu-Jui Yvonne Wan

Research output: Contribution to journalArticle

47 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2761-2774
Number of pages14
JournalDigestive Diseases and Sciences
Volume53
Issue number10
DOIs
StatePublished - Oct 2008
Externally publishedYes

Fingerprint

S-Adenosylmethionine
Fatty Liver
Choline
Methionine
Diet
Liver
Fibrosis
Non-alcoholic Fatty Liver Disease
Methionine Adenosyltransferase
Thioacetamide
Lipids
Lipid Metabolism
Chemokines
Hepatocellular Carcinoma
Homeostasis
Maintenance
Alcohols

Keywords

  • Fatty liver
  • Hepatitis
  • Methionine adenosyltransferase
  • Methylation

ASJC Scopus subject areas

  • Gastroenterology

Cite this

The transition from fatty liver to NASH associates with SAMe depletion in db/db mice fed a methionine choline-deficient diet. / Wortham, Matthew; He, Lin; Gyamfi, Maxwell; Copple, Bryan L.; Wan, Yu-Jui Yvonne.

In: Digestive Diseases and Sciences, Vol. 53, No. 10, 10.2008, p. 2761-2774.

Research output: Contribution to journalArticle

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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.",
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