l-carnitine protects against bile acid-induced mitochondrial dysfunction and IGF-1 impairment in hepatocyte cultures

Excessive amounts of bile acids (ΒΑ) exert hepatotoxic effects. We investigated the effects of glycochenodeoxycholic acid (GCDC) on mitochondrial function and insulin-like growth factor-1 (IGF-1) activity in hepatocytes and also examined if l -carnitine (CRNT) has any protective role. Primary hepatocyte cultures were treated with 0–100 μM GCDC with or without 5 mM l -carnitine (CRNT). DNA synthesis was measured by bromodeoxyuridine incorporation assay. Enzymic activities of carnitine palmitoyltransferase-1 (CPT-1), cytochrome c oxidase (CcO) and medium chain-acylCoA dehydrogenase (MCAD), were measured in hepatocyte homogenates. Expression of peroxisome proliferator activated receptor gamma coactivator 1-α (PGC-1α) and IGF-1 receptor (IGF-1R) was detected by RT- PCR and Western blot analysis, respectively . Treatment with GCDC significantly decreased the enzymatic activity of MCAD, CPT-1 and CcO ( P < 0.01), and mitochondrial ATP content. Additionally, GCDC significantly increased malondialdehyde (MDA) levels in mitochondria and downregulated PGC-1α ( p < 0.01). Furthermore, the IGF-1-induced DNA synthesis and IGF-1R gene expression were also notably reduced in GCDC-treated hepatocytes. However, co-treatment with 5 mM CRNT markedly abrogated the GCDC-induced impairment of CcO activity and PGC-1α downregulation, while it had no effect on MCAD activity. In addition, CRNT treatment also restored the enzymatic activity of CPT-1 and the gene expression levels of IGF-1 in GCDC-treated hepatocytes ( p < 0.05). GCDC-induced hepatotoxic effects could be triggered by mitochondrial dysfunction and impairment of IGF-1 activity. CRNT has potential beneficial effects against ΒΑ-induced cytotoxicity via enhancing the CPT-1 and CcO enzyme activities, and ATP production in addition to upregulation of PGC-1α and IGF-1R. • Bile acid, Glycochenodeoxycholic acid (GCDC), impairs mitochondrial activity and, downregulates IGF-1 function through IGF-1 receptor modulation in hepatocyte cultures. • l -carnitine induces gene expression of IGF-1 receptor and PGC-1 a and, mitigates GCDC-induced mitochondrial dysfunction and IGF-1 impairment. • This study demonstrates that IGF-1 impairment might be involved in hepatotoxic effects of bile acids.