title: Prevention of free fatty acid-induced hepatic lipotoxicity by carnitine via reversal of mitochondrial dysfunction.
abstract: BACKGROUND
  Mitochondria are the main sites for fatty acid oxidation and play a central role in lipotoxicity and nonalcoholic steatohepatitis.
  
  
  OBJECTIVE
  We investigated whether carnitine prevents free fatty acid (FFA)-induced lipotoxicity in vitro and in vivo.
  
  
  METHODS
  HepG2 cells were incubated with FFA, along with carnitine and carnitine complexes. Mitochondrial β-oxidation, transmembrane potential, intracellular ATP levels and changes in mitochondrial copy number and morphology were analysed. Otsuka Long-Evans Tokushima Fatty and Long-Evans Tokushima Otsuka rats were segregated into three experimental groups and fed for 8 weeks with (i) normal chow, (ii) a methionine choline-deficient (MCD) diet or (iii) an L-carnitine-supplemented MCD diet.
  
  
  RESULTS
  Carnitine prevented FFA-induced apoptosis (16% vs. 3%, P < 0.05). FFA treatment resulted in swollen mitochondria with increased inner matrix density and loss of cristae. However, mitochondria co-treated with carnitine had normal ultrastructure. The mitochondrial DNA copy number was higher in the carnitine treatment group than in the palmitic acid treatment group (375 vs. 221 copies, P < 0.05). The carnitine group showed higher mitochondrial β-oxidation than did the control and palmitic acid treatment groups (597 vs. 432 and 395 ccpm, P < 0.05). Carnitine treatment increased the mRNA expression of carnitine palmitoyltransferase 1A and peroxisome proliferator-activated receptor-γ, and carnitine-lipoic acid further augmented the mRNA expression. In the in vivo model, carnitine-treated rats showed lower alanine transaminase levels and lesser lobular inflammation than did the MCD-treated rats.
  
  
  CONCLUSIONS
  Carnitine and carnitine-lipoic acid prevent lipotoxicity by increasing mitochondrial β-oxidation and reducing intracellular oxidative stress.
authors.affiliation: Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Korea. noshin@hanyang.ac.kr
authors.forename: Dae Won
authors.initials: DW
authors.lastname: Jun
authors.forename: Won Kyeong
authors.initials: WK
authors.lastname: Cho
authors.forename: Jin Hyun
authors.initials: JH
authors.lastname: Jun
authors.forename: Hyuk Jin
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Ki-Seok
authors.initials: KS
authors.lastname: Jang
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Hye Jun
authors.initials: HJ
authors.lastname: Jeon
authors.forename: Kang Nyeong
authors.initials: KN
authors.lastname: Lee
authors.forename: Hang Lak
authors.initials: HL
authors.lastname: Lee
authors.forename: Oh Young
authors.initials: OY
authors.lastname: Lee
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Yoon
authors.forename: Ho Soon
authors.initials: HS
authors.lastname: Choi
authors.forename: Joon Soo
authors.initials: JS
authors.lastname: Hahm
authors.forename: Min Ho
authors.initials: MH
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002331:Carnitine / Q000031:analogs & derivatives / Q000494:pharmacology*; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D002796:Choline Deficiency / Q000150:complications; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008715:Methionine / Q000172:deficiency; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D008063:Thioctic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D004272:DNA, Mitochondrial; D005230:Fatty Acids, Nonesterified; D047495:PPAR gamma; D012333:RNA, Messenger; D008063:Thioctic Acid; D000255:Adenosine Triphosphate; D008715:Methionine; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine