|Budget Amount *help
¥3,000,000 (Direct Cost : ¥3,000,000)
Fiscal Year 1998 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Fiscal Year 1997 : ¥1,800,000 (Direct Cost : ¥1,800,000)
High density lipoprotein (HDL), an antiatherogenic lipoprotein comprises several subclasses differing in composition and metabolic function. This physiological complexity appears to be matched with the growing number of candidate HDL receptors, since several HDL binding proteins have recently been identified in various tissues. It is important to identify their structure and potential role in HDL metabolism. We have cloned a candidate HDL receptor, HB2, which is one of a pair of HDL binding proteins (HBl and HB2) first purified from rat liver. To elucidate the regulation and function of HB2, we studied the effect of cytokines, bile acids and fat-soluble vitamins, which are known to affect gene expression, on the HB2 expression. HB_2, minimally present in monocytic THP-1 cells, is substantially upregulated in phorbol ester (PMA)-differentiated macrophages and appears sensitive to cholesterol loading of these cells. Although Insulin and IGF-1 did not influence HB2 expression, some cytokines, TNF-alpha, IL-6 and M-CSF, strongly reduced expression of HB2 in THP-1 cells. It is known that bile acids up-regulate expression of genes related to cholesterol metabolism. Taurocholate and chenodeoxycholate also increased HB2 expression significantly.- Retinol and 1,25-vitamin D_3 did not change HB2 expression, however, 25-vitamin D_3 increased HB2 mRNA in THP-1 cells. alpha-Tocopherol significantly reduced HB2 mRNA expression in PMA-differentiated THP- 1 macrophages.
To elucidate whether an l-IMG-CoA reductase inhibitor affects mRNA levels of HB2 expression, we investigated the effect of simvastatin in rabbits. After three weeks administration of simvastatin, cholesterol contents in liver and lung were decreased. Simvastatin treatment significantly reduced the levels of HB2 mRNA in the liver and lung of rabbits Suppression of HB2 may also be antiatherogenic ; therefore it is an another feature of HMG-CoA reductase inhibitors.