IGF-1 Suppresses Cholesterol Accumulation in the Liver of Growth Hormone Deficiency Mice Via Activation of ABCA1

Presentation Number: SAT 426
Date of Presentation: April 1st, 2017

Kensaku Fukunaga*1, Hitomi Imachi1, Jingya Lyu1, Xiaozhou Zhang1, Tao Dong1, Seisuke Sato1, Tomohiro Ibata1, Nao Yamaji1, Kazuko Yonezaki1, Fumi Kikuchi1, Takuo Yoshimoto1 and Koji Murao2
1Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan, 2Kagawa University, Miki-cho,Kita-Gun,Kagawa, Japan

Abstract

Background: Adult growth hormone deficiency (AGHD) is characterized by increased visceral adiposity, abnormal lipid profiles, premature atherosclerosis, and increased mortality. Recently, several clinical studies suggest that AGHD is associated with an increased prevalence of fatty liver, NAFLD and then progression to NASH. As a mechanistic insight, growing evidences have revealed that GH as well as IGF-I play essential roles in inducing a formation of fatty liver. ATP-binding cassette transporter A1 (ABCA1), a 254-kD cytoplasmic membrane protein, is a pivotal regulator of lipid efflux from cells to apolipoproteins and plays an important role in reverse cholesterol transport. It was identified as a mutated molecular in Tangier Disease (TD) and absence of ABCA1 induces HDL deficiency, the deposition of sterol in tissue, and severe fatty liver. Although it should be noted that fatty liver/NAFLD/NASH has emerged as an important comorbidity in AGHD, the precise roles of GH/IGF-I on cholesterol accumulation in liver have not been clarified yet.

Purpose: In this study, we checked the effects of IGF-1 on ABCA1 expression in GH deficiency mice to clarify its effects on lipid metabolism.

Methods and results: We used western blot, real-time PCR to confirm that IGF-1 up-regulated the expression of ABCA1 in HepG2 cells. We confirmed that IGF-1 increased the promoter activity of ABCA1 using luciferase report system, and we found that the inhibitor of PI3K pathway could inhibit the increased effect of IGF-1 on ABCA1 promoter activity.

We measured the cholesterol content and stained HepG2 cells with Oil Red O and found that IGF-1 decreased the cholesterol accumulation in the cell line. In vivo experiments, 8-week old mice were divided into 2 groups (n=5 each): High Fat Diet (HFD, 45 kcal % fat, 20 kcal % protein, and 35 kcal % carbohydrate) plus 2.5mg/kg/every other day Pegvisomant (PEG: growth hormone receptor antagonist) via intraperitoneal (IP) injection; and High Fat Diet plus PEG plus 2.4mg/kg/day IGF-1 via IP injection. After the continuous 4 weeks administration of PEG and/or IGF-1, we employed biochemical analysis, histological analysis of the liver and the expression of ABCA1 in the liver of those mice. Serum ALT and HDL-cholesterol level were significantly decreased in PEG+IGF-1 group compared with PEG group. In histological analysis of the PEG group, HE staining revealed steatosis of the liver and its change was restored in PEG+IGF-1 group. The expression of ABCA1 in the liver was significantly increased in PEG+IGF-1 group compared to that in PEG group by western blot or real time PCR.

Conclusion: Our data shows that IGF-1 suppresses cholesterol accumulation in liver by accumulation of ABCA1 expression via the signal transduction pathway, PI3K pathway, raised the possibility that IGF-1 may be of therapeutic value in the treatment of disease such as fatty liver.

 

Nothing to Disclose: KF, HI, JL, XZ, TD, SS, TI, NY, KY, FK, TY, KM