| Popis: |
With the increasing incidence of obesity, super- and malnutrition in Western countries, fatty acid and lipid-induced metabolic diseases have become a growing problem. In particular, nonalcoholic fatty liver disease (NAFLD) which is associated with an increased risk of cardiometabolic dysfunction and diabetes type 2 affects a rising proportion of the world’s population. Fatty liver, a reversible condition and the initial stage in the pathogenesis of NAFLD can progress to severe acute and chronic liver disorders, including nonalcoholic steatohepatitis, liver fibrosis/cirrhosis and hepatocellular carcinoma. Dysfunction in hepatocellular lipid metabolism and subsequent hepatocyte lipoapoptosis by accumulation of fatty acids are strongly implicated in disease progression. The initial step in fatty acid and lipid metabolism is the activation of long chain fatty acids to acyl-CoAs which is catalyzed by long chain acyl-CoA synthetases (ACSL). Of the five mammalian ACSL isoformes known, ACSL5 is the only one that is located on mitochondria and potentially involved in apoptosis regulation. The goal of the present study was to characterize the role of ACSL5 in NAFLD pathogenesis and, particularly, to analyze its function in fatty liver manifestation and progression to hepatocellular apoptosis. Using in vivo and in vitro models of hepatocyte steatosis as well as plasmid-mediated stable gene transfer and small interfering RNA-mediated gene silencing, it was demonstrated that ACSL5 expression was strongly induced by fatty acid uptake and lipid accumulation in hepatocytes. Overexpression of ACSL5 decreased hepatocyte viability and increased susceptibility to TRAIL and TNFα, whereas knock down of ACSL5 reduced apoptosis susceptibility in fatty acid-treated hepatocytes. Lipid analytical mass spectrometry revealed the involvement of hepatic sphingolipid metabolism in ACSL5-induced apoptosis sensitization. By channelling acyl-CoAs into sphingolipid metabolism, high ACSL5 activity increased de novo synthesis of proapoptotic sphingolipids including ceramide and sphingosine. Furthermore, ACSL5 induced structural modifications of mitochondria and mediated activation of mitochondrial apoptosis signalling. In summary, this study gives evidence that ACSL5 plays a putative role in promoting fatty acid-induced lipoapoptosis in hepatocytes and ACSL5-associated lipid de novo synthesis in the pathogenesis of NAFLD. |
