Is lipotoxicity caused by the intracellular accumulation ofacyl CoA ?

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Long chain fatty acid is thought to be a strong cause of hyperglycemia (Lipotoxicity). This concept is accepted by most investigators. However, the intracellular mechanism remains unclear. Therefore, we analyzed as follows.1. Juvenile visceral steatosis (JVS) mouse, which we reported in 1991, serves as an animal model of primary carnitine deficiency. Because JVS mouse has a defective carnitine transporter (octn 2) and intracellular carnitine level remains low, long chain acyl-CoA is supposed to be accumulated in pancreatic islet cells or cardiac myocytes. Therefore we analyzed the islets and heart.(1) Size of islet of JVS mouse was small. By HE staining, content of glucagon was maintained, however content of pancreatic polypeptide was decreased. Some cells conserved the amount of insulin, but some did not.(2) Carnitine transport activity in cultured myocyte of JVS mouse was decreased by about 20 percent of normal control at 25 μ M free carnitine level which is the physiological concentration in serum. Free carnitine level in JVS mouse heart is about 1-2 percent of normal control. In such a case, uptake rate of 2-deoxyglucose was eleven times higher than that of control.2. To know the mechanism the fatty acid toxicity on β -cell function, insulinoma cell line INS-1 was incubated with palmitate. Palmitate caused the accumulation of triacylglycerol and expression rate (phosphorylated Akt/Akt) was increased. Also, activation of NFk β signal transduction was observed. Therefore, it is suggested that metabolic derangement by long-chain fatty acid was, in part, caused by phosphorylated Akt and activated NFk β signal transduction.3. Diabetic heart showed a higher Ca^<2+> content and it was inhibited by T_3.