Prevention of free fatty acid‐induced hepatic lipotoxicity by carnitine via reversal of mitochondrial dysfunction

• DOI: 10.1111/j.1478-3231.2011.02602.x
• Publication Date: 2011-08-03T18:33:48Z
• Authors: Dae Won Jun; Won Kyeong Cho; Jin Hyun Jun; Hyuk Jin Kwon; Ki‐Seok Jang; Hyun‐Jeong Kim; Hye Jun Jeon; Kang Nyeong Lee; Hang Lak Lee; Oh Young Lee; Byung Chul Yoon; Ho Soon Choi; Joon Soo Hahm; Min Ho Lee
• Keywords: Membrane Potential, Mitochondrial; 0301 basic medicine; Carnitine O-Palmitoyltransferase; Apoptosis; Mitochondria, Liver; Hep G2 Cells; Fatty Acids, Nonesterified; DNA, Mitochondrial; Choline Deficiency; 3. Good health; Fatty Liver; Disease Models, Animal; 03 medical and health sciences; Adenosine Triphosphate; Methionine; Gene Expression Regulation; Liver; Non-alcoholic Fatty Liver Disease; Carnitine; Animals; Humans; Lysosomes; Oxidation-Reduction

AbstractBackground:Mitochondria are the main sites for fatty acid oxidation and play a central role in lipotoxicity and nonalcoholic steatohepatitis.Aims: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.