지질대사 이상 질환에서 핵 수용체 LXR의 역할 및 기전에 대한 연구 : Role of liver X receptors in the pathogenesis of lipid metabolism disorders
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- 약학대학 약학과
- Issue Date
- 서울대학교 대학원
- Hepatitis B Virus ; HBx ; Liver X Receptor ; Hepatocellular carcinogenesis ; Hepatosteatosis ; Hypoxia ; HIF-1α ; Foam cell ; Atherosclerosis
- 학위논문 (박사)-- 서울대학교 대학원 : 약학과, 2013. 2. 이미옥.
- The liver X receptors (LXRs) are nuclear receptors that are activated by endogenous oxysterols, oxidized derivatives of cholesterol. The LXRs are involved in the process of reverse cholesterol transport which is the process by which the lipoprotein particle, HDL, carries cholesterol from the peripheral tissues to the liver and play a critical role in metabolic abnormalities, including insulin resistance, obesity, dyslipidemia and hypertention.
The first part of this study describes the role of LXRs in hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma. Several studies have suggested that infection by HBV genotypes B is associated with an increased risk of HCC
however, the molecular mechanism by which HBV induces events leading to HCC has not been clearly elucidated. In this study, HBx induced expression of LXRs and its lipogenic target genes, which was accompanied by the accumulation of lipid droplets. RNA interference of LXRα or β expression effectively blocked the amount of lipid droplets as well as the expression of the lipogenic genes, indicating that the HBx-induced lipogenesis was LXR-dependent. HBx and LXRα are physically associates in the nucleus. HBx enhanced transactivation function of LXRα by recruiting CBP to the SREBP-1c promoter. Furthermore, the expression of LXRs was significantly increased in the liver of HBx-transgenic mice. Finally, there was a significant increase in the expression of LXRα and its lipogenic target genes in human HBV-associated HCC specimens. These results suggest a novel association between HBx and LXR-induced hepatic lipogenesis, which may constitute a pivotal molecular mechanism underlying the development of HBV-associated HCC.
The second part of this study describes the role of cross-talk between LXRα and HIF-1α for the formation of triglyceride-rich foam cells during the development of atherosclerosis. Atherosclerosis is characterized by subendothelial accumulation of lipid-rich macrophages, called foam cells. Hypoxic conditions in the atherosclerotic lesions contribute to the formation of these lipid-loaded macrophages. The liver X receptor is a regulator of lipid metabolism in many tissues, however, role of LXRα in the foam cell formation is not known. In this study, the expression of LXRα was time-dependently induced under hypoxia in human primary macrophages and RAW 264.7 cells. Knockdown of HIF-1α using si-RNA completely abolished the induction of LXRα and its target genes indicating that the induction of LXRα was HIF-1α dependent. TO901317, an activator of LXRα, enhanced the expression level and the transcriptional activity of HIF-1α, which was also decreased by knockdown of LXRα. Second, LXRα increased HIF-1α protein stability through a physical interaction between the ligand binding domain of LXRα and the oxygen-dependent degradation domain of HIF-1α. Third, the activation of HIF-1α or LXRα synergistically induced triglyceride accumulation in the macrophages. Finally, LXRα and HIF-1α were codistributed in the macrophages of atherosclerotic arteries obtained from patients. These results suggest that the positive feedback regulation of transcriptional induction and protein stability of LXRα and HIF-1α may have an important impact for foam-cell formation and the development of atherosclerotic lesions.
Taken together, it is suggested that that the molecular mechanism of LXR activation may turn on a vicious cycle of lipid production and inflammation in the lipid metabolism disorder.
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- College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Theses (Ph.D. / Sc.D._약학과)
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