title: L-serine supplementation attenuates alcoholic fatty liver by enhancing homocysteine metabolism in mice and rats.
abstract: BACKGROUND
  Hyperhomocysteinemia plays an important role in the development of hepatic steatosis, and studies indicate that homocysteine-lowering treatment inhibits the development of fatty liver.
  
  
  OBJECTIVE
  We evaluated the effects of L-serine on alcoholic fatty liver and homocysteine metabolism.
  
  
  METHODS
  In a binge ethanol study, male C57BL/6 mice were divided into 4 groups: control, ethanol + vehicle, and ethanol + 20 or 200 mg/kg L-serine. Mice were gavaged with ethanol (5 g/kg body weight) 3 times every 12 h with or without L-serine which was given twice 30 min before the last 2 ethanol doses. Control mice were fed isocaloric dextran-maltose. In a chronic ethanol study, male Wistar rats were divided into 3 groups: control, ethanol, and ethanol + L-serine. Rats were fed a standard Lieber-DeCarli ethanol diet (36% ethanol-derived calories) for 4 wk with or without dietary L-serine supplementation (1%; wt:vol) for the last 2 wk. In control rats, the ethanol-derived calories were replaced with dextran-maltose. The effects of L-serine were also tested in AML12 cells manipulated to have high homocysteine concentrations by silencing the genes involved in homocysteine metabolism.
  
  
  RESULTS
  Binge ethanol treatment increased serum homocysteine and hepatic triglyceride (TG) concentrations by >5-fold vs. controls, which were attenuated in the 200-mg/kg L-serine treatment group by 60.0% and 47.5%, respectively, compared with the ethanol group. In the chronic ethanol study, L-serine also decreased hepatic neutral lipid accumulation by 63.3% compared with the ethanol group. L-serine increased glutathione and S-adenosylmethionine by 94.0% and 30.6%, respectively, compared with the ethanol group. Silencing betaine homocysteine methyltransferase, cystathionine β-synthase, or methionine increased intracellular homocysteine and TG concentrations by >2-fold, which was reversed by L-serine when L-serine-independent betaine homocysteine methyltransferase was knocked down.
  
  
  CONCLUSIONS
  These results demonstrate that L-serine ameliorates alcoholic fatty liver by accelerating L-serine-dependent homocysteine metabolism.
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; and.
authors: Woo-Cheol
authors: WC
authors: Sim
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; and.
authors: Hu-Quan
authors: HQ
authors: Yin
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; and.
authors: Ho-Sung
authors: HS
authors: Choi
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; and.
authors: You-Jin
authors: YJ
authors: Choi
authors: College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors: Hui Chan
authors: HC
authors: Kwak
authors: College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors: Sang-Kyum
authors: SK
authors: Kim
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; and lee@snu.ac.kr.
authors: Byung-Hoon
authors: BH
authors: Lee
mesh_terms: D000818:Animals; D050940:Betaine-Homocysteine S-Methyltransferase / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D019587:Dietary Supplements; D002149:Energy Intake; D000431:Ethanol / Q000008:administration & dosage; D005235:Fatty Liver, Alcoholic / Q000188:drug therapy*; D006710:Homocysteine / Q000097:blood / Q000378:metabolism*; D020138:Hyperhomocysteinemia / Q000188:drug therapy; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017208:Rats, Wistar; D012436:S-Adenosylmethionine / Q000378:metabolism; D012694:Serine / Q000008:administration & dosage*; D014280:Triglycerides / Q000097:blood
chemical_list: D014280:Triglycerides; D006710:Homocysteine; D000431:Ethanol; D012694:Serine; D012436:S-Adenosylmethionine; D008715:Methionine; D050940:Betaine-Homocysteine S-Methyltransferase; D003541:Cystathionine beta-Synthase
keywords: SREBP1; alcoholic fatty liver; homocysteine; nutrition and disease; sulfur amino acid metabolism