A pharmacologic increase in activity of plasma transaminase derived from small intestine in animals receiving an acyl CoA: diacylglycerol transferase (DGAT) 1 inhibitor

Abstract

Acyl CoA: diacylglycerol acyltransferase (DGAT) 1 is an enzyme that catalyzes the re-synthesis of triglycerides (TG) from free fatty acids and diacylglycerol. JTT-553 is a DGAT1 inhibitor and exhibits its pharmacological action (inhibition of re-synthesis of TG) in the enterocytes of the small intestine leading to suppression of a postprandial elevation of plasma lipids. After repeated oral dosing JTT-553 in rats and monkeys, plasma transaminase levels were increased but there were neither changes in other hepatic function parameters nor histopathological findings suggestive of hepatotoxicity. Based on the results of exploratory studies for investigation of the mechanism of the increase in transaminase levels, plasma transaminase levels were increased after dosing JTT-553 only when animals were fed after dosing and a main factor in the diet contributing to the increase in plasma transaminase levels was lipids. After dosing JTT-553, transaminase levels were increased in the small intestine but not in the liver, indicating that the origin of transaminase increased in the plasma was not the liver but the small intestine where JTT-553 exhibits its pharmacological action. The increase in small intestinal transaminase levels was due to increased enzyme protein synthesis and was suppressed by inhibiting fatty acid-transport to the enterocytes. In conclusion, the JTT-553-related increase in plasma transaminase levels is considered not to be due to release of the enzymes from injured cells into the circulation but to be phenomena resulting from enhancement of enzyme protein synthesis in the small intestine due to the pharmacological action of JTT-553 in this organ.

Effects of 1,25(OH)2D3 on lipid droplet growth in adipocytes

“…TG is synthesized in cells mainly through the G3P and MAG pathways. 38 In this study, ACSL3, GPAT3/4, AGPAT1, and PAP expressions were all significantly increased after PA intervention in lipidogenic 3T3-L1 cells compared with those in the control group cells. TG is mainly synthesized from exogenous fatty acids in DGAT1 and endogenous fatty acids, namely de novo fatty acids, in DAGT2.…”

Specificity of transaminase activities in the prediction of drug-induced hepatotoxicity

“…After repeated oral dosing of a DGAT1 inhibitor in rats and monkeys, plasma transaminase levels were increased but there were neither changes in other hepatic function parameters nor histopathological findings suggestive of hepatotoxicity (Yokoyama et al, 2018). The increase in plasma transaminase levels was noted in monkeys at lower dose levels with lower systemic exposure than in rats (AUC: 9 to 33 μg•hr/mL at 1 mg/kg and AUC: 221 to 395 μg•hr/mL at 100 mg/kg in monkeys and rats, respectively) and monkeys were more sensitive than rats for the elevation of transaminases.…”

“…The transaminase elevations with these profiles can be called "pharmacology-related transaminase elevations". This definition is supported by evidence that the transaminase elevations in drugs modifying glucose/lipid metabolism can be cancelled by inhibition of the pharmacological actions of these drugs, as shown in statins by supplementation with mevalonic acid, α-GIs with feeding of high glucose levels and DGAT1 inhibitor with a lipase inhibitor or by knockdown of either IRE1α or c-Jun in the MTP inhibitor (Gerson et al, 1989;Bomhard et al, 1996;Bomhard, 1996;Yokoyama et al, 2018;Josekutty et al, 2013).…”

“…The findings related to the pharmacological action of the DGAT1 inhibitor, including decreased plasma triglyceride levels and accumulation of fatty acids in the epithelial cells in the small intestine, were noted in monkeys at lower dose levels than in rats. Based on the results of exploratory studies for investigation of the mechanism of the increase in transaminase levels, plasma transaminase levels were increased even after single oral dosing the DGAT1 inhibitor only when animals were fed after dosing and a main factor in the diet contributing to the increase in plasma transaminase levels was lipids (Yokoyama et al, 2018). After dosing the DGAT1 inhibitor, transaminase activities were increased in the small intestine but not in the liver, indicating that the origin of transaminase increased in the plasma was not the liver but the small intestine, where the DGAT1 inhibitor exhibits its pharmacological action.…”

“…After dosing the DGAT1 inhibitor, transaminase activities were increased in the small intestine but not in the liver, indicating that the origin of transaminase increased in the plasma was not the liver but the small intestine, where the DGAT1 inhibitor exhibits its pharmacological action. The increase in small intestinal transaminase levels was due to increased enzyme protein synthesis and was suppressed by co-administration of orlistat (a lipase inhibitor), which inhibits fatty acid-transport to the enterocytes (Yokoyama et al, 2018). Interestingly, the plasma transaminase that was increased after dosing the DGAT1 inhibitor in dogs, in which AST activity is much higher than ALT activity in the small intestine, was AST, not ALT, and the response to the DGAT1 inhibitor in dogs was different from that in rats and monkeys, in both of which ALT activity is equal to or higher than AST activity in the small intestine.…”