PMID- 18498552
OWN - NLM
STAT- MEDLINE
DCOM- 20080701
LR  - 20211020
IS  - 1530-0277 (Electronic)
IS  - 0145-6008 (Print)
IS  - 0145-6008 (Linking)
VI  - 32
IP  - 6
DP  - 2008 Jun
TI  - Effect of transgenic extrahepatic expression of betaine-homocysteine 
      methyltransferase on alcohol or homocysteine-induced fatty liver.
PG  - 1049-58
LID - 10.1111/j.1530-0277.2008.00666.x [doi]
AB  - BACKGROUND: Chronic alcohol feeding induces hyperhomocysteinemia (HHcy). 
      Previously, we reported a protective role of betaine-homocysteine 
      methyltransferase (BHMT) in homocysteine-induced injury in cultured hepatocytes. 
      In this study, we investigated the direct role of BHMT in alcohol or 
      homocysteine-induced liver injury. METHODS: Betaine-homocysteine 
      methyltransferase transgenic (Tg) mice were generated. Comparisons were made 
      between the Tg and wild type (WT) mice in their response to intragastric alcohol 
      infusion or to oral feeding of a high methionine low folate diet (HMLF). RESULTS: 
      Expression of the Tg BHMT was increased in organs peripheral to the liver. The 
      alcohol infusion for 4 weeks increased: plasma ALT by 5-fold in WT mice and 
      2.7-fold in Tg mice; plasma homocysteine by 7-fold in WT mice and 2-fold in Tg 
      mice; liver triglycerides by 4-fold in WT mice and 2.5-fold in Tg mice. The 
      alcohol-induced fatty liver was more severe in WT than in Tg mice based on H&E 
      staining. The HMLF feeding for 4 weeks increased plasma ALT by 2-fold in WT mice 
      and 1-fold in Tg mice; plasma homocysteine by 21-fold in WT mice and 3.3-fold in 
      Tg mice; liver triglycerides by 2.5-fold in WT mice and 1.5-fold in Tg mice. HMLF 
      induced accumulation of macro fat droplets in WT but not Tg mice. Betaine 
      supplementation decreased partially the alcohol or HMLF-induced increase of ALT, 
      homocysteine and liver lipids in WT mice. However, Tg mice were normal when fed 
      both HMLF and betaine. In WT mice, both alcohol and HMLF induced moderate 
      increase of sterol regulatory element binding protein 1 (SREBP1) protein which 
      was partially reduced by betaine supplementation. In Tg mice, alcohol but not 
      HMLF increased SREBP1. Carbohydrate responsive element-binding protein was 
      increased by alcohol in either WT or Tg mice which was not affected by betaine 
      supplementation. Ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine 
      (SAH) was reduced by 50% in WT and by 20% in Tg mice fed alcohol. Ratio of 
      phosphatidylcholine (PC) to phosphatidylethanolamine (PE) was reduced in WT but 
      not Tg mice fed alcohol. Changes in PE methyltransferase activities were not 
      detected in response to alcohol or HMLF feeding but were increased by betaine. 
      CONCLUSIONS: The BHMT Tg mice are resistant to alcohol or HMLF-induced HHcy and 
      liver steatosis indicating that peripheral metabolism of homocysteine protected 
      the liver without a direct effect of BHMT in the liver. Multiple mechanisms are 
      involved in protection by betaine including increased SAM/SAH and PC/PE ratios.
FAU - Ji, Cheng
AU  - Ji C
AD  - Research Center for Liver Disease, Southern California Research Center for 
      Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine, University of 
      Southern California, Los Angeles, California 90033, USA. chengji@usc.edu
FAU - Shinohara, Masao
AU  - Shinohara M
FAU - Vance, Dennis
AU  - Vance D
FAU - Than, Tin Aung
AU  - Than TA
FAU - Ookhtens, Murad
AU  - Ookhtens M
FAU - Chan, Christine
AU  - Chan C
FAU - Kaplowitz, Neil
AU  - Kaplowitz N
LA  - eng
GR  - P50AA11999/AA/NIAAA NIH HHS/United States
GR  - R01 AA014428/AA/NIAAA NIH HHS/United States
GR  - P30DK048522/DK/NIDDK NIH HHS/United States
GR  - P30 DK048522-14/DK/NIDDK NIH HHS/United States
GR  - R01 AA014428-05/AA/NIAAA NIH HHS/United States
GR  - P30 DK048522/DK/NIDDK NIH HHS/United States
GR  - P50 AA011999/AA/NIAAA NIH HHS/United States
GR  - R01 AA014428-5/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Alcohol Clin Exp Res
JT  - Alcoholism, clinical and experimental research
JID - 7707242
RN  - 0 (Recombinant Proteins)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 3K9958V90M (Ethanol)
RN  - 935E97BOY8 (Folic Acid)
RN  - AE28F7PNPL (Methionine)
RN  - EC 2.1.1.5 (Betaine-Homocysteine S-Methyltransferase)
SB  - IM
MH  - Animals
MH  - Betaine-Homocysteine S-Methyltransferase/*genetics/*physiology
MH  - Diet
MH  - Ethanol/administration & dosage
MH  - Fatty Liver/chemically induced/*prevention & control
MH  - Fatty Liver, Alcoholic/*prevention & control
MH  - Folic Acid/administration & dosage
MH  - *Gene Expression
MH  - Homocysteine/*adverse effects
MH  - Humans
MH  - Methionine/administration & dosage
MH  - Mice
MH  - Mice, Transgenic
MH  - Recombinant Proteins/genetics
PMC - PMC2596885
MID - NIHMS79996
EDAT- 2008/05/24 09:00
MHDA- 2008/07/02 09:00
PMCR- 2008/12/06
CRDT- 2008/05/24 09:00
PHST- 2008/05/24 09:00 [pubmed]
PHST- 2008/07/02 09:00 [medline]
PHST- 2008/05/24 09:00 [entrez]
PHST- 2008/12/06 00:00 [pmc-release]
AID - ACER666 [pii]
AID - 10.1111/j.1530-0277.2008.00666.x [doi]
PST - ppublish
SO  - Alcohol Clin Exp Res. 2008 Jun;32(6):1049-58. doi: 
      10.1111/j.1530-0277.2008.00666.x.