Molecular biological studies on the formation of atherogenic small dense low density lipoprotein (sLDL)

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We have systematically investigated the mechanism of formation of small dense low density lipoprotein (sLDL) in the circulation which is known to be one of risk factors for atherosclerosis. As sLDL is high frequently found on patients with type IV hypertriglyceridemia, we first attempted to clarify an underlying etiology of type IV hypertriglyceridemia by monitoring LPL immunoreactive mass in postheparin plasma of 32 non-diabetic patients with type IV hypertriglyceridemia using our sandwich-EIA technique for the first screenig, followed by a second screening for LPL gene aberrations using PCR-SSCP and direct sequencing methods. By this approach, we found that heterozygous LPL deficiency was an underlying genetic disorder of type IV hypertriglyceridemia, and that subjects with heterozygous LPL deficiency are prone to manifest type IV hypertriglyceridemia when they acquire triglyceride (TG) synthesis stimulating factors like high alcohol intake.In order to understand the mechanism of the formation of sLDL under hypertriglyceridemia, lipoproteins isolated from 30 subjects with type IV hypertriglyceridemia and 30 normal subjects were compared. The ratio of TG over cholesterol ester (CE) in HDL (HDL-TG/CE) was correlated with serum TG concentration derived from TG-rich lipoproteins such as VLDL.Factors correlating with LDL size variation were further searched, and the variation of LDL size was reversely correlated with HDL-TG/CE ratio and hepatic triglyceride lipase (HTGL) immunoreactive mass in PHP.These statistical data were confirmed by in vitro experiments in which lipid composition of HDL is changed into TG-rich and CE-poor particle via lipid transfer protein action by interacting with high amount of VLDL corresponding to type IV hypertriglyceridemia, and LDL is converted into TG-rich and CE-poor particle by interacting with TG-rich/CE-poor HDL,and in the final step TG hydrolysis of LDL by HTGL action results in the formation of sLDL.