Tu1814 GLP-1R Agonist Increased Glucose Uptake and Inhibited GSK3ß Phosphorylation Through the AMPK Signaling Pathways in Human Hepatocytes

Abstract

A S L D A b st ra ct s and liver cholesterol levels were measured. We compared gene expression profiles of liver specimen from MCD diet fed mice with those from MCS diet fed mice, and examined the effect of exendin-4 on gene expression profiles in the liver on MCD diet fed mice, using Agilent whole mouse genome oligo microarrays (Agilent Technologies). We also performed a cholesterol biosynthesis pathway analysis significantly affected transcripts of the liver. Results: While serum cholesterol levels were significantly decreased by MCD diet, exendin4 had a tendency to decrease serum cholesterol levels. On the other hand, hepatic cholesterol levels were significantly increased by MCD diet compared with those by MCS diet. Exendin4 significantly decreased MCD diet-induced increase of hepatic cholesterol levels compared with saline. Transcripts for 6476 mRNAs differed in expression patterns > 2 fold between MCS diet and MCD diet with saline groups. Furthermore, transcripts for 7740 mRNAs differed in expression patterns > 2 fold between MCD diet with saline groups and MCD diet with exendin-4. The pathway of gene expressions most impacted by MCD diet was cholesterol biosynthesis. MCD diet up-regulated cholesterol biosynthesis signaling. In contrast, exendin-4 down-regulated cholesterol biosynthesis signaling. Conclusions: Exendin4 inhibited MCD diet-induced increase of hepatic cholesterol levels through the inhibition of cholesterol biosynthesis. These results indicate that exendin-4 may decrease hepatic cholesterol resulting in the attenuation of hepatic inflammation in NASH model.