Abstract
Microsomal triglyceride transfer protein (MTP) is a target to reduce plasma lipids because of its indispensable role in triglyceride-rich lipoprotein biosynthesis. MTP inhibition in Western diet fed mice decreased plasma triglycerides/cholesterol, whereas increasing plasma alanine/aspartate aminotransferases (ALT/AST) and hepatic triglycerides/free cholesterol. Free cholesterol accumulated in the endoplasmic reticulum (ER) and mitochondria resulting in ER and oxidative stresses. Mechanistic studies revealed that MTP inhibition increased transcription of the GPT/GOT1 genes through up-regulation of the IRE1α/cJun pathway leading to increased synthesis and release of ALT1/AST1. Thus, transcriptional up-regulation of GPT/GOT1 genes is a major mechanism, in response to ER stress, elevating plasma transaminases. Increases in plasma and tissue transaminases might represent a normal response to stress for survival.
Background: Microsomal triglyceride transfer protein (MTP) inhibition augments plasma transaminases, however, mechanisms are unknown.
Results: MTP inhibition increased endoplasmic reticulum (ER) stress and induced GPT/GOT1 transcription through the Ire1α/cJun pathway.
Conclusion: Transcriptional up-regulation and increased synthesis contribute to augmentations in plasma ALT/AST.
Significance: Increased transcription of the transaminase genes may reflect a mechanism for hepatocyte survival after ER stress.