Hepatic clearance of plasma low density lipoproteins.

An elevated plasma LDL concentration is a major risk factor for the development of atherosclerosis and coronary heart disease. The concentration of LDL in plasma is determined, to a large extent, by events in the liver, since this organ is the source of LDL (via VLDL) and is the major site of LDL catabolism. LDL uptake by the liver is mediated largely by receptor-dependent mechanisms and fully 80 to 90% of whole body receptor-dependent LDL catabolism occurs in the liver. The rate of receptor-dependent LDL uptake by the liver is influenced by dietary and genetic factors. Cholesterol and fatty acids are the major dietary factors that alter receptor-dependent LDL uptake by the liver and appear to do so by regulating LDL receptor gene transcription. Regulation of LDL receptor gene transcription by sterols is mediated by sterol regulatory elements within the LDL receptor promoter, but how the nucleus actually senses cellular cholesterol levels and how dietary fatty acids might influence this process remain to be elucidated. Genetic factors may affect the basal rate of receptor-dependent LDL transport or the sensitivity of the LDL receptor pathway to regulation by dietary lipids. An understanding of how dietary lipids regulate hepatic LDL transport and plasma LDL levels, and identification of the major genetic factors that determine responsiveness to dietary lipids is crucial to the development of safe and effective dietary guidelines and to the selection of individuals most likely to benefit from diet modification.