SATURATED FATTY-ACIDS AND LDL RECEPTOR MODULATION IN HUMANS AND MONKEYS

It has been known for 40 years that dietary saturated fat (SAT FAT) in creases plasma cholesterol, including LDL-C and HDL-C. In humans, wher e LDL-C is typically > 90 mg/dl this SAT FAT effect largely reflects c hanges in LDL-C pool size. The original human studies suggested that L DL-C expansion during SAT FAT consumption reflected reduced LDL cleara nce (LDL receptor activity) in hyperlipemics and increased LDL product ion rates in normolipemics (LDL-C < 100 mg/dl). This dual explanation is supported by data from several animal models where specific saturat ed fatty acids (SFAs) have been the focus. However, the situation is c omplicated by the fact that polyunsaturated fatty acids (PUFAs) oppose SFAs, i.e. PUFAs decrease LDL-C and increase LDL receptor (LDLr) acti vity, so the effect of SAT FAT intake may represent the combined influ ence of increased SFAs and decreased PUFAs. In fact, careful scrutiny of primate data suggests a negligible effect of saturated fat on LDL c learance (and receptor activity) in the absence of dietary cholesterol when PUFA intake is adequate (5-10%en) and the lipoprotein profile is relatively normal (LDL-C < 90 mg/dl), i.e. normolipemic situations at the time of dietary intervention. In such cases increases in LDL-C du e to SFAs (particularly 12:0+14:0) appear to reflect LDL overproductio n associated with a shift in cholesterol from tissues to the plasma ch olesteryl ester (CE) pool (both LDL-C and HDL-C) without altering whol e-body cholesterol balance. The reason for this shift, which is accomp anied by an increase in the plasma oleic/linoleic CE ratio, is unknown but may reflect a decreased rate of CE hydrolysis by the liver. When individuals or animals are rendered hyperlipemic by other factors (e.g . chronic caloric and dietary cholesterol excesses in humans or by cho lesterol feeding in animals) specific SFAs (particularly 16:0) can con tribute to decreased LDLr activity initiated by a primary factor, such as dietary cholesterol. However, LDLr down-regulation by dietary chol esterol greatly exceeds any contribution from SFAs.