Effect of transgenic extrahepatic expression of betaine-homocysteine methyltransferase on alcohol or homocysteine-induced fatty liver.
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.
Ji
Cheng
C
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
Shinohara
Masao
M
Vance
Dennis
D
Than
Tin Aung
TA
Ookhtens
Murad
M
Chan
Christine
C
Kaplowitz
Neil
N
D000818:Animals; D050940:Betaine-Homocysteine S-Methyltransferase / Q000235:genetics* / Q000502:physiology*; D004032:Diet; D000431:Ethanol / Q000008:administration & dosage; D005234:Fatty Liver / Q000139:chemically induced / Q000517:prevention & control*; D005235:Fatty Liver, Alcoholic / Q000517:prevention & control*; D005492:Folic Acid / Q000008:administration & dosage; D015870:Gene Expression; D006710:Homocysteine / Q000009:adverse effects*; D006801:Humans; D008715:Methionine / Q000008:administration & dosage; D051379:Mice; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000235:genetics
D011994:Recombinant Proteins; D006710:Homocysteine; D000431:Ethanol; D005492:Folic Acid; D008715:Methionine; D050940:Betaine-Homocysteine S-Methyltransferase