Mitochondrial-Derived Peptide MOTS-c promotes hepatic fatty acid metabolism and regulation by metformin. Ramanjaneya M1, Jerobin J1, Bettahi I1, Sivaraman SK1, ¬ Mohammad RM1, Skarulis MC1 and Abou-Samra AB1. 1Translational Research Institute, Academic Health System and Department of Medicine, Hamad Medical Corporation, Doha, Qatar. Objectives: Mitochondrial dysfunction contributes to the pathogenesis of metabolic disorders and is a leading cause for development of insulin resistance. This is promoted, at least partly, through lipid accumulation in ectopic tissues, including liver (non-alcoholic fatty liver disease) and skeletal muscle. The role of mitochondria as functional organelles, and the signaling molecules produced by them are critical for cellular energy homeostasis. Dysfunction in mitochondria contributes to the pathogenesis of metabolic disorders. MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) encoding a 16-amino-acid peptide is a recently identified peptide. The skeletal muscle appears to be the main target organ for MOTS-c and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c promotes glucose utilization, insulin sensitivity and metabolic homeostasis through activation of AMPK dependent mechanisms in skeletal muscle. MOTS-c protects rodents against diet and ageing induced insulin resistance. However the role of MOTS-c hepatocytes is unknown. In this current study we aimed to study the functional importance of MOTS-c on liver fatty acid metabolism in using HepG2 hepatocytes model. Methods: Analysis of MOTS-c gene expression in human tissue panel: Human tissue cDNA panel was obtained from Clontech. MOTS-c gene expression in various human tissues was measured by real-time PCR. Human hepatocytes (HepG2) cells were used for this study: Cells were maintained as subconfluent monolayers in DMEM (Invitrogen) with 10% fetal bovine serum and 100 units/ml penicillin plus 100 μg/ml streptomycin (Invitrogen) at 37 °C with 5% CO2. For all stimulation experiments cells were grown for overnight in 2% serum containing media. Fatty acid-induced steatosis: Approximately 80% confluence were pretreated with MOTS-c and further stimulated for 24 hrs with oleic acid and palmitic acid 1:2 ratio in 2%-serum medium for 24 hrs in 12-well culture plate. Following this incubated with nile red solution for 20 mins and then subjected to flow cytometric analysis to measure lipid accumulation in HepG2 cells. Control cells were treated with fatty acid-free medium containing albumin. Effects of antidiabetic drugs on MOTS-c expression: Approximately about 80% confluent cells were stimulated with commonly used antidiabetic drugs insulin 100 nM, rosiglitazone 2 mM or metformin 1 mM for 24 in 2%-serum medium 12-well culture plate. Following this MOTS-c secretion was measured using commercially available elisa kits. Results: MOTS-c gene transcripts are expressed in human liver and HepG2 cells. Stimulation of HepG2 cells with MOTS-c suppresses fatty acid synthase (FAS), sterol regulatory element-binding protein-1c (SREBP1c) and acetyl-CoA carboxylase (ACC) the key genes required for hepatic lipid production. Further MOTS-c reduced fatty acid induced hepatic lipid accumulation. Conclusion: Our primary result indicates that MOTS-c promotes hepatic fatty acid metabolism through down-regulation of multiple genes involved in fatty acid metabolism in liver. Further studies are in progress to assess the effects of anti-diabetic drugs such as metformin, insulin and rosiglitazone on MOTS-c secretion. The findings from this study are of clinical importance given that non-alcoholic liver disease (NAFLD) is highly prevalent in obese and diabetes subjects in Qatar. MOTS-c and its agonists have potential to be used as therapeutic agents for treatment of NAFLD.


Article metrics loading...

Loading full text...

Full text loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error