Biologically active low density lipoprotein in human peripheral lymph.

In vivo regulation of human mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase. Decreased enzyme catalytic efficiency in familial hypercholesterolemia.

“…Consistent with this prediction is the finding that, in normal cultured cells transferred from lipoprotein-replete to lipoprotein-deficient media, HMG CoA reductase synthesis is derepressed to a level of enzyme activity similar to that observed in FH homozygous cells cultured in dilute serum or in lipoprotein-deficient medium (7). Finally, many investigators have reported that the high levels of HMG CoA reductase activity are not altered in cultured cells from homozygous FH patients by short-term exposure to concentrations of LDL cholesterol that markedly inhibit the enzyme in normal cells (3,6,7,30,31). In virtually all these experiments, however, medium concentrations of lipoprotein cholesterol did not exceed 200 mg/dl.…”

Lysosomal unesterified cholesterol content correlates with liver cell death in murine Niemann-Pick type C disease

“…However, the tight endothelial lining of most capillary beds limits the access of circulating lipoproteins to these LDLRs in most organs, including the central nervous system (25). The concentration of LDL in peripheral lymph, for example, is only 5-10% of that found in the plasma (26,27).…”

Physiological Level of LDL Cholesterol: The Master Key A Nobel Dream Comes True

“…In 1975, Keys [2] based on several epidemiological studies [3][4][5] reported that LDL-C levels in industrialized societies compared with those in non-industrialized societies were excessively high; he also established that LDL-C levels in non-human mammals are less than 50 mg/dL, similar to those of newborn human mammals, and that in the latter, the LDL-C levels are doubled in adolescence and quadrupled in adulthood ( Figure 1). In 1978, the English group of Reich and Myant in collaboration with the American group of Brown and Goldstein [6] demonstrated that, in "in vitro" studies with the use of radioactive I-labeled LDL, LDL receptors (LDLR) were saturated with an average plasma LDL level of 25 mg/dL, equivalent to 2.5 mg/dL in lymph (Figure 2), likewise, they demonstrated that with this LDL level, the enzymatic activity of the Hydroxy-MethylGlutaryl-Coenzyme-A Reductase (HMGCoAR)-pivotal enzyme of the cellular cholesterol synthesis was completely inhibited. Finally, in 1979, Bilheimer who at that time was a collaborator of Goldstein and Brown and tutor of Grundy and Stone (collaborators of the work referred to and ultimately lead authors of ATP III and IV) [7] and in 1981, Kovanen [8] in pharmacokinetic studies of lipoproteins, confirmed that, in dogs, chimpanzees and humans, LDL production is similar, about 15 mg/kg weight; however, the elimination of such lipoprotein differs significantly between the three mammalian species; Bilheimer and Kovanen reported that the elimination of LDL expressed as the "Fractional Catabolic Rate" (FCR) or the ratio between the "pool" of circulating LDL and the "pool" eliminated was 1.6 in dogs, 0.8 in chimpanzees and 0.4 in humans , this reduction in FCR being the variable that explained the differences in the circulating level of LDL-C, 25 mg/dL in the dog, 50 mg/dL in the chimpanzee, and ≥ 100 mg/dL in the adult human ( Figure 3).…”

“…At a 25 mg/dL LDL plasma concentration (left) or at a 2.5 mg/dL lymph concentration (right), it is observed that the uptake of I 125 -labeled LDL is virtually non-existent, which translates the RLDLs saturation [6].…”

“…[5] The protein content and esterified cholesterol of LDL are hydrolyzed. [6] Cholesterol is transported hydrophobically to the membranes of the RE-AG system or is re-esterified by the ACAT-2 effect.…”