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 while 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. We also observed that IRE1α/cJun pathway is involved in augmenting plasma ALT/AST in mice fed methionine-choline deficient diet. Thus, transcriptional up-regulation of GPT/GOT1 genes is a major mechanism elevating plasma transaminases under different conditions.
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