Page 238 - ebook

[D. Medicine/Translational Research] D-3

Macrophage inhibitory cytokine-1 aggravated diet-induced

gallstone formation via increased ABCG5, ABCG8 expressions

Kim MinHee¹,², Park Joo-Won², Kim Su-Jeong¹, Park Inkeun³, Park Woo-Jae¹*

¹Biochemistry, Gachon University College of Medicine, Incheon 21999, Korea, ²Biochemistry, Ewha Womans

University College of Medicine, Seoul 07804, Korea, ³Internal Medicine, Gachon Univeristy Gil Medical Center,

Incheon 21565, Korea

Macrophage inhibitory cytokine-1 (MIC-1) is known to be associated with cachexia, however, the effects of MIC-1
on bile acid metabolism and gallstone formation are poorly understood. In this study, we investigate the mechanism

of MIC-1 on bile acid metabolism and gallstone formation. Hepatic cholesterol and bile acid levels are reduced
upon MIC-1 injection and SREBP-2, a master regulator of cholesterol metabolism, and HMG-CoA reductase (HMGCR)

expressions are reduced. Furthermore, the expressions of Cyp7a1, Cyp27a1, and Cyp7b1, are decreased. We find
that AMPK phosphorylation is elevated upon MIC-1 treatment. AICAR, an AMPK activator, also reduces Cyp7a1 and

HMGCR expressions, while compound C, an AMPK inhibitor, reversed MIC-1-induced Cyp7a1 and HMGCR reductions.
Furthermore, total biliary cholesterol levels in MIC-1 injected mice are increased with increased ABCG5/8 expressions.

Liver X receptor α, β (LXRα, β), LRH1, HNF4α, NR1I3(CAR) expressions, which are upstream of ABCG5/8, are not
affected, but MIC-1 treatment increases ABCG5/8 expressions and promoter activities. In conclusion, MIC-1 increases

AMPK phosphorylation, which affect Cyp7a1 and HMGCR reductions, and ABCG5/8 expressions, which affects
gallstone formation.