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

Background: 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 beta-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 beta-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-gamma, 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 beta-oxidation and reducing intracellular oxidative stress.This work was supported by the Bio-Meditech Regional Innovation Center at Eulji University, under the Regional Innovation Center Program of the Ministry of Commerce, Industry and Energy