Insulin Resistance (IR) plays a key role in pathogenesis of type 2 diabetes. NAFLD, considered by some as the hepatic manifestation of IR, leads to NASH, cirrhosis and rarely hepatocellular carcinoma. Hepatic Cirrhosis secondary to NAFLD is an emerging public health tsunami. IR is known to impair lipid induced hepatic Retinoid metabolism. Lecithin: Retinol Acyl Transferase (Lrat) plays a crucial role in retinoid homeostasis. Studies have shown the involvement of all-trans Retinoic Acid (atRA) in mitochondrial biogenesis; it functions mainly through PPAR-α and RXR. We identified overexpression of LRAT in liver of HFD-fed rats, hepG2 and huh7 cell lines. Lipid (Palmitic acid-PA) induced over expression of Lrat was associated with a significant reduction in RA production; thereby impairing PPAR-α mediated fatty acid oxidation (FAO) and fat accumulation in hepatocytes. PA induced overexpression of hepatic Lrat was accompanied by excess lipid influx into the mitochondria resulting in impaired mitochondrial biogenesis and bioenergetics, characterized by loss of membrane potential, elevated ROS generation and impaired FAO. Knockdown of Lrat gene restored reduced levels of PPARα resulting from overexpression of Lrat upon PA treatment. Silencing of hepatic Lrat abrogated neutral fat accumulation in PA treated liver tissue and cell lines. Lipid induced mitochondrial dysfunction and resulting elevation in ROS levels was associated with increased mitochondrial fragmentation and decreased membrane potential; Lrat silencing reversed this process. Taken together our study unravels a novel role of PA induced Lrat overexpression in neutral fat accumulation in the liver that may potentially lead to development of NAFLD and NASH in the short term and cirrhosis and rarely, HCC in the long term. This brings to the fore Lrat silencing as a future drug target to prevent and/or treat fat accumulation in the liver in setting of Insulin Resistance.
E. Karmakar: None. N. Das: None. S. Mukhopadhyay: None. S. Roy: None.