Low Density Lipoprotein Catabolism Research Articles

Plasma lipids, lipoprotein composition and profile during induction and treatment of hepatic lipidosis in cats and the metabolic effect of one daily meal in healthy cats.

Anorexia in obese cats may result in feline hepatic lipidosis (FHL). This study was designed to determine plasma lipids and lipoprotein profiles in queens at different stages during experimental induction of FHL (lean, obese, FHL), and after 10 weeks of treatment. Results were compared with those obtained from lean queens of same age fed the same diet but at a maintenance level, once a day. Hepatic lipidosis led to an increase in plasma triacylglycerol (TG), very low density lipoprotein (VLDL) and low density lipoprotein (LDL), and an enrichment of LDL with TG and of high density lipoprotein (HDL) with cholesterol, suggesting that VLDL secretion is enhanced, VLDL and LDL catabolism is lowered, and lipoprotein exchanges are impaired in FHL. This study also showed that cholesterolaemia is increased in cats fed at a dietary rhythm of one meal per day compared to ad libitum feeding.

Increased binding of LDL and VLDL to apo B,E receptors of hepatic plasma membrane of rats treated with Fibernat.

Research has focussed on the hypocholesterolemic effects of certain types of dietary fiber such as enhancing conversion of hepatic cholesterol to bile acids or increase in catabolism of low density lipoprotein (LDL) via the apo B,E receptor. The effect of oral administration of a unique fibre cocktail of fenugreek seed powder, guar gum and wheat bran (Fibernat) and its varied effects on some aspects of lipid metabolism and cholesterol homeostasis in rats were examined. Rats were administered Fibernat along with the atherogenic diet containing 1.5 % cholesterol and 0.1 % cholic acid. Amounts of hepatic lipids, hepatic and fecal bile acids and activity of hepatic triglyceride lipase (HTGL) were determined. Transmission electron microscopic examination of the liver tissue and extent of uptake of (125)I-LDL and (125)I-VLDL by the hepatic apo B,E receptor was carried out. Food intake and body weight gain were similar between the 3 different dietary groups. Fibernat intake significantly increased apo B,E receptor expression in rat liver as reflected by an increase in the maximum binding capacity (B(max)) of the apo B,E receptor to (125)I-LDL and (125)I-VLDL. The activity of HTGL was increased by approximately 1.5-fold in Fibernat-fed rats as compared to those fed the atherogenic diet alone. A marked hypocholesterolemic effect was observed. Cholesterol homeostasis was achieved in Fibernat-fed rats. Two possible mechanisms are postulated to be responsible for the observed hypocholesterolemic effect a) an increase in conversion of cholesterol to bile acids and b) possibly by intra-luminal binding which resulted in increased fecal excretion of bile acids and neutral sterols. The resulting reduction in cholesterol content of liver cells coupled with upregulation of hepatic apo B,E receptors and increased clearance of circulating atherogenic lipoproteins-LDL and very low density lipoprotein (LDL and VLDL)-is the main mechanism involved in the hypocholesterolemic effect of Fibernat. The results suggest that Fibernat's effect on plasma LDL concentration is also possibly mediated by increased receptor-mediated catabolism of VLDL. Thus, Fibernat therapy is an effective adjunct to diet therapy and might find potential use in the therapy of hyperlipidemic subjects.

Autosomal recessive hypercholesterolemia: genetics and clinical aspects

In the last 10 years, new types of genetic hypercholesterolemia, different from familial hypercholesterolemia (FH) or familial defective apo B (FDB), have been reported; these forms have both autosomal dominant or recessive inheritance. Starting in 1995, we have described a new recessive type of hypercholesterolemia, named ARH. This disease, initially reported in one Sardinian family, is characterized by a severe increase of low-density lipoproteins (LDL) in plasma, xanthomas, xanthelasmas, and premature coronary heart disease. The family showed presence of consanguinity, bimodal distribution of cholesterol levels, and absence of vertical transmission. We have demonstrated that this hypercholesterolemia is due to a marked reduction of LDL catabolism that is caused by a selective reduction of LDLs uptake by the liver. The gene responsible for ARH maps to chromosome 1p35. It codes for an adaptor protein that interacts with the NPXY sequence in the cytoplasmic tail of LDL-R, and is necessary for the functioning of LDL-R in liver, but not in fibroblasts. Only two mutations were identified in Sardinia; a single base pair insertion in exon 4 (ARH1), and a nonsense mutation at codon 22 (ARH2). The high frequency of ARH in the island is probably due to a combination of genetic drift, consanguinity, and geographic isolation.

Effect of atorvastatin on apolipoprotein B100 containing lipoprotein metabolism in type-2 diabetes.

Seven hypertriglyceridemic patients with type-2 diabetes were treated with atorvastatin (40 mg/day) for 2 months. Kinetics of apolipoprotein B100 (apoB100)-containing lipoproteins were determined before and after atorvastatin treatment and compared with data obtained in five normolipidemic volunteers. ApoB100 metabolism was studied using stable isotopes and multicompartmental modeling. Compared with normolipidemic obese subjects, type-2 diabetic patients had a higher apoB100 concentration in very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and low-density lipoproteins (LDL) (P < 0.005). Kinetic analysis showed an increase in the total apoB100 production rate (P < 0.005) related to VLDL apoB100 overproduction (P < 0.005). Patients were also characterized by a lower fractional catabolic rate (FCR) in VLDL (not significant) or IDL (P < 0.005) mainly related to a decrease in VLDL and IDL delipidation rate (P < 0.005). Catabolism of LDL was also lower in diabetic patients (P < 0.05). Atorvastatin treatment significantly decreased plasma triglycerides (P < 0.05), total and LDL cholesterol (P < 0.05), apoB100 in LDL, IDL, and VLDL (P < 0.05). Treatment significantly decreased total apoB100 production rate (P < 0.05), but only for VLDL (P < 0.05). Treatment normalized FCR in IDL and LDL (P < 0.05). We concluded that atorvastatin improved lipid abnormalities in type-2 diabetic patients not only by increasing the clearance of apoB100-containing lipoproteins but also by decreasing VLDL production.

Platelet factor 4 binds to low-density lipoprotein receptors and disrupts the endocytic itinerary, resulting in retention of low-density lipoprotein on the cell surface

The influence of platelets on the cellular metabolism of atherogenic lipoproteins has not been characterized in detail. Therefore, we investigated the effect of platelet factor 4 (PF4), a cationic protein released in high concentration by activated platelets, on the uptake and degradation of low-density lipoprotein (LDL) via the LDL receptor (LDL-R). LDL-R-dependent binding, internalization, and degradation of LDL by cultured cells were inhibited 50%, 80%, and 80%, respectively, on addition of PF4. PF4 bound specifically to the ligand-binding domain of recombinant soluble LDL-R (half-maximal binding 0.5 microg/mL PF4) and partially (approximately 50%) inhibited the binding of LDL. Inhibition of internalization and degradation by PF4 required the presence of cell-associated proteoglycans, primarily those rich in chondroitin sulfate. PF4 variants with impaired heparin binding lacked the capacity to inhibit LDL. PF4, soluble LDL-R, and LDL formed ternary complexes with cell-surface proteoglycans. PF4 induced the retention of LDL/LDL-R complexes on the surface of human fibroblasts in multimolecular clusters unassociated with coated pits, as assessed by immuno-electron microscopy. These studies demonstrate that PF4 inhibits the catabolism of LDL in vitro in part by competing for binding to LDL-R, by promoting interactions with cell-associated chondroitin sulfate proteoglycans, and by disrupting the normal endocytic trafficking of LDL/LDL-R complexes. Retention of LDL on cell surfaces may facilitate proatherogenic modifications and support an expanded role for platelets in the pathogenesis of atherosclerosis.

Policosanol: Clinical pharmacology and therapeutic significance of a new lipid-lowering agent

Background Policosanol is a mixture of higher primary aliphatic alcohols isolated from sugar cane wax, whose main component is octacosanol. The mixture has been shown to lower cholesterol in animal models, healthy volunteers, and patients with type II hypercholesterolemia. Methods We reviewed the literature on placebo-controlled lipid-lowering studies using policosanol published in peer-reviewed journals as well as studies investigating its mechanism of action and its clinical pharmacology. Results At doses of 10 to 20 mg per day, policosanol lowers total cholesterol by 17% to 21% and low-density lipoprotein (LDL) cholesterol by 21% to 29% and raises high-density lipoprotein cholesterol by 8% to 15%. Because higher doses have not been tested up to now, it cannot be excluded that effectiveness may be even greater. Daily doses of 10 mg of policosanol have been shown to be equally effective in lowering total or LDL cholesterol as the same dose of simvastatin or pravastatin. Triglyceride levels are not influenced by policosanol. At dosages of up to 20 mg per day, policosanol is safe and well tolerated, as studies of >3 years of therapy indicate. There is evidence from in vitro studies that policosanol may inhibit hepatic cholesterol synthesis at a step before mevalonate generation, but direct inhibition of the hydroxy-methylglutaryl–coenzyme A reductase is unlikely. Animal studies suggest that LDL catabolism may be enhanced, possibly through receptor-mediated mechanisms, but the precise mechanism of action is not understood yet. Policosanol has additional beneficial properties such as effects on smooth muscle cell proliferation, platelet aggregation, and LDL peroxidation. Data on efficacy determined by clinical end points such as rates of cardiac events or cardiac mortality are lacking. Conclusions Policosanol seems to be a very promising phytochemical alternative to classic lipid-lowering agents such as the statins and deserves further evaluation. (Am Heart J 2002;143:356-65.)

Cholesterol and apolipoprotein B metabolism in Tangier disease

Tangier disease (TD), caused by mutations in the gene encoding ATP-binding cassette 1 (ABCA1), is a rare genetic disorder in which homozygotes have a marked deficiency of high density lipoproteins (HDL), as well as concentrations of low density lipoproteins (LDL) that are typically 40% of normal. Although it is well known that the reduced levels of HDL in TD are due to hypercatabolism, the mechanism responsible for the low LDL levels has not been defined. Recently, it has been reported that intestinal cholesterol absorption is altered in ABCA1 deficient mice, suggesting that aberrant cholesterol metabolism may contribute to the LDL reductions in TD. In order to explore this possibility, as well as to define the role that ABCA1 plays in the metabolism of apolipoprotein (apoB)-containing lipoproteins, we determined the kinetics of apoB-100 within lipoproteins, and cholesterol absorption, biosynthesis, and turnover, in a compound heterozygote for TD. The levels of HDL cholesterol, LDL cholesterol and LDL apoB-100 in this subject were 7, 27 and 69% of normal, respectively, the latter of which was due to a two-fold increase in LDL catabolism (0.54 vs. 0.26±0.07 pools day −1) relative to controls ( n=11). NMR analysis of plasma lipoproteins revealed that 91% of the LDL cholesterol in the TD subject was contained within small, dense LDL, as compared with only 20% for controls ( n=70). Cholesterol absorption was 97% of the value for controls ( n=15) in the TD subject, at 45%, with cholesterol synthesis and turnover increased modestly by 17 and 25%, respectively. Our data are consistent with the concept that the reductions of LDL observed in TD are due to enhanced catabolism, secondary to changes in LDL composition and size, with neither cholesterol absorption nor metabolism significantly influenced by mutations in ABCA1.

Exercise training accelerates low-density lipoprotein catabolism as evaluated by a cholesterol-rich emulsion

Exercise training accelerates low-density lipoprotein catabolism as evaluated by a cholesterol-rich emulsion

Increased LDL cholesterol and atherosclerosis in LDL receptor-deficient mice with attenuated expression of scavenger receptor B1.

Scavenger receptor BI (SR-BI) is a multiligand cell-surface receptor that plays a central role in high density lipoprotein homeostasis in rodents. To investigate a role for SR-BI in atherosclerosis, mice with attenuated SR-BI expression were crossed with low density lipoprotein (LDL) receptor-deficient mice. Compound-homozygous mutants showed increased plasma cholesterol, surprisingly due primarily to increased LDL cholesterol and apolipoprotein B levels. LDL turnover studies showed that this resulted from increased LDL cholesterol production rather than decreased LDL catabolism. Atherosclerotic lesion size was significantly increased in male compound-mutant mice relative to LDL receptor-deficient controls (93 427+/-16 079 versus 34 448+/-5 331 microm(2), respectively; P=0.003). The proatherogenic effect of attenuated SR-BI expression may in part be due to increased LDL cholesterol levels. These findings suggest that upregulation of the receptor could have therapeutic potential for the treatment of atherosclerosis.

Analysis of low-density lipoprotein catabolism by primary cultures of hepatic cells from normal and low-density lipoprotein receptor knockout mice

Low-density lipoproteins (LDL) are taken up by LDL receptor (LDLr)-dependent and -independent pathways; the role and importance of the latest being less well defined. We analyzed the importance of these pathways in the mouse by comparing LDL binding to primary cultures of hepatocytes from LDLr knockout (LDLr KO) and normal C57BL/6J mice. Saturation curve analysis shows that 125I-LDL bind specifically to normal and LDLr KO mouse hepatocytes with similar dissociation constants ( K d) (31.2 and 22.9 μg LDL-protein/ml, respectively). The maximal binding capacity ( B max) is, however, reduced by 48% in LDLr KO mouse hepatocytes in comparison to normal hepatocytes. Conducting the assay in the presence of a 200-fold excess of high-density lipoprotein-3 (HDL3) reduced by 39% the binding of 125I-LDL to normal hepatocytes and abolished the binding to the LDLr KO mouse hepatocytes. These data indicate that in normal mouse hepatocytes, the LDLr is responsible for approximately half of the LDL binding while a lipoprotein binding site (LBS), interacting with both LDL and HDL3, is responsible for the other half. It can also be deduced that both receptors/sites have a similar affinity for LDL. The metabolism of LDL-protein and cholesteryl esters (CE) was analyzed in both types of cells. 125I-LDL-protein degradation was reduced by 95% in LDLr KO hepatocytes compared to normal hepatocytes. Comparing the association of 125I-LDL and 3H-CE-LDL revealed a CE-selective uptake of 35.6- and 22-fold for normal and LDLr KO mouse hepatocytes, respectively. Adding a 200-fold excess of HDL3 in the assay reduced by 71% the CE-selective uptake in LDLr KO hepatocytes and by 96% in normal hepatocytes. This indicates that mouse hepatocytes are able to selectively take up CE from LDL by the LBS. The comparison of LDL-CE association also showed that the LBS pathway provides 5-fold more LDL-CE to the cell than the LDLr. Overall, our results indicate that in mouse hepatocytes, LDLr is almost completely responsible for LDL-protein degradation while the LBS is responsible for the major part of LDL-CE entry by a CE-selective uptake pathway.

Effects of continuous conjugated estrogen and micronized progesterone therapy upon lipoprotein metabolism in postmenopausal women

AbstractThe effects of continuously administering both conjugated equine estrogens (CEE) and micronized progesterone (MP) on the concentration, composition, production and catabolism of very low density (VLDL) and low density lipoproteins (LDL) have not previously been reported. The mechanism of the hormonally induced reductions of plasma LDL cholesterol of Sf 0–20 (mean 16%, P < 0.005) and LDL apoB (mean 6%, P < 0.025) were investigated by studying the kinetics of VLDL and LDL apolipoprotein (apo) B turnover after injecting autologous 131I-labeled VLDL and 125I-labeled LDL into each of the 6 moderately hypercholesterolemic postmenopausal subjects under control conditions and again in the fourth week of a 7-week course of therapy (0.625 mg/d of CEE + 200 mg/d of MP). The combined hormones significantly lowered plasma LDL apoB by increasing the mean fractional catabolic rate of LDL apoB by 20% (0.32 vs. 0.27 pools/d, P < 0.03). Treatment also induced a significant increase in IDL production (6.3 vs. 3.7 mg/kg/d, P = 0.028). However, this did not result in an increase in LDL production because of an increase in IDL apoB direct catabolism (mean 102%, P = 0.033). VLDL kinetic parameters were unchanged and the concentrations of plasma total triglycerides (TG), VLDL-TG, VLDL-apoB did not rise as often seen with estrogen alone. Plasma HDL-cholesterol rose significantly (P < 0.02). Our major conclusion is that increased fractional catabolism of LDL underlies the LDL-lowering effect of the combined hormones. —Wolfe, B. M., P. H. R. Barrett, L. Laurier, and M. W. Huff. Effects of continuous conjugated estrogen and micronized progesterone therapy upon lipoprotein metabolism in postmenopausal women. J. Lipid Res. 2000. 41: 368–375.

Enhancement of low density lipoprotein catabolism by non-steroidal anti-inflammatory drugs in cultured HepG2 cells

Several clinical studies have shown that different types of non-steroidal anti-inflammatory drugs (NSAIDs) can reduce the cholesterol content of atherosclerotic blood vessels. The mechanism of this reduction is not established. One possibility is that NSAIDs affect low density lipoprotein (LDL) catabolism. In this study, we investigated the effect of the NSAIDs, indomethacin, flufenamic acid, ibuprofen, acetaminophen, and also acetylsalicylic acid on LDL binding, cell-association and degradation in cultured hepatoma HepG2 cells. LDL was labelled with 125 I to study LDL catabolism. Furthermore, dextran sulphate, a substance that is known to release bound LDL from its receptors, was used to study LDL receptor activity. Reverse transcription-polymerase chain reaction was used to study the messenger RNA (mRNA) of LDL receptor. Our results show that flufenamic acid, indomethacin, and to a lesser extent ibuprofen, and acetaminophen increase LDL binding, cell-association, and degradation. Flufenamic acid was most potent and increased LDL catabolism by 50–70%, whereas acetylsalicylic acid had only a modest effect. Also, flufenamic acid and indomethacin were both found to increase the synthesis of mRNA of the LDL receptor with a subsequent increase of LDL receptor protein. We also investigated the effect of indomethacin on LDL binding in the presence of the 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase inhibitor, fluvastatin. We found that both indomethacin and fluvastatin had an additive up-regulatory effect on LDL receptor activity. In addition the effect of flufenamic acid on cell-associated LDL was examined in the presence of cyclosporine, which is known to decrease LDL catabolism. The results show that flufenamic acid can restore the inhibitory effect of cyclosporine. The study thus shows that NSAIDs enhance LDL catabolism due to increased synthesis of the mRNA for LDL receptor protein. This action might contribute to the lipid-lowering effect of NSAIDs.

Lifibrol enhances the low density lipoprotein apolipoprotein B-100 turnover in patients with hypercholesterolemia and mixed hyperlipidemia

Lifibrol (4-(4′-tert-butylphenyl)-1-(4′carboxyphenoxy)-2-butanol), a new hypocholesterolemic drug, effectively reduces total cholesterol (CH), low density lipoprotein (LDL)-CH, and apolipoprotein (apo) B in experimental animals and in humans. The impact of Lifibrol on the metabolism of apoB-100 containing lipoproteins in patients with hyperlipoproteinemia using endogenous labeling with stable isotopes is examined. Kinetic studies were performed in four male hypercholesterolemic individuals (type IIa) before and on treatment with 450 mg of Lifibrol daily for 4 weeks, and in five male individuals suffering from mixed hyperlipidemia (type IIb) before and on therapy for 12 weeks. Kinetic parameters were estimated by multicompartmental modeling. Lifibrol therapy reduced total CH by 16% ( P=0.012) in all patients, increased triglycerides (TG) by 11% (not significant) in type IIa patients and decreased TG by 34% ( P=0.059) in type IIb patients. During Lifibrol therapy, LDL apoB-100 concentrations decreased by 19% ( P=0.011) in all patients. The decrease in LDL apoB concentrations with Lifibrol therapy was due to an overall increase (75%, P=0.006) of the fractional catabolic rates (FCR) of LDL apoB. This increase was partially attenuated by a 33% increase in LDL apoB production rate (PR) ( P=0.041). The overall production of apoB increased only slightly. Our data suggest that the major mechanism by which Lifibrol lowers LDL-CH is an increase in receptor-mediated catabolism of LDL rather than a decrease in hepatic apoB production.

Evidence of circadian rhythm in low-density lipoprotein apoB catabolism and its impact on the estimation of kinetic parameters.

Compartmental models with constant parameters are commonly used in kinetic analysis of low-density lipoproteins (LDLs). Recent studies in animals have demonstrated the existence of circadian rhythms (CRs) in cholesterol synthesis and LDL catabolism. In this study, we investigated the possible existence of a CR in the fractional catabolic rate (FCR) of LDL apoB in man. Radioactivity data from 45 turnover studies using 125I-labelled LDL apoB were analysed. In a preliminary analysis the pattern of radioactivity decay was investigated. Kinetic analysis was performed by using one- and two-compartment models with constant parameters (steady-state, SS, analysis). Parameters were estimated by the use of the whole data set, which included frequent sampling during the first day of the turnover study, or the once-a-day data, taken at 08.00 h. The selection of once-a-day data allowed elimination of the impact of a CR on parameter evaluation. Furthermore, non-steady-state (NSS) analysis was performed in which the FCR of LDL apoB was calculated as a function of time. In one additional subject, the FCR of LDL apoB was calculated separately for the day and the night using the urine-to-plasma (U/P) radioactivity ratio. The presence of a CR in LDL apoB catabolism, with higher FCR values during the day than during the morning, was demonstrated by the NSS analysis and confirmed by LDL apoB calculation from the U/P ratio. The SS analysis with the whole and the once-a-day data sets resulted in similar average FCR of apoB values (0.329 +/- 0.076 and 0.321 +/- 0.071 respectively) when the two-compartment model was used. Thus, a CR appeared to have little impact on the average FCR of apoB estimation. However, frequent sampling used in the hope of improving parameter estimation accuracy actually resulted in deterioration of the intercompartmental parameter estimators. The fractional catabolic rate of LDL apoB exhibited a circadian rhythm with higher FCR values during the day than during the morning. The presence of a CR had, however, a limited impact on the overall FCR of apoB values.

Characterization of a new form of inherited hypercholesterolemia: familial recessive hypercholesterolemia.

We previously described a Sardinian family in which the probands had a severe form of hypercholesterolemia, suggestive of familial hypercholesterolemia (FH). However, low density lipoprotein (LDL) receptor activity in fibroblasts from these subjects and LDL binding ability were normal. The characteristics of the pedigree were consistent with an autosomal recessive trait. Sitosterolemia and pseudohomozygous hyperlipidemia were ruled out. A second Sardinian kindred with similar characteristics was identified. Probands showed severe hypercholesterolemia, whereas their parents and grandparents were normolipidemic. FH, familial defective apoprotein (apo) B, sitosterolemia, and cholesteryl ester storage disease were excluded by in vitro studies. We addressed the metabolic basis of this inherited disorder by studying the in vivo metabolism of LDL in 3 probands from these 2 families. 125I-LDL turnover studies disclosed a marked reduction in the fractional catabolic rate (0.19+/-0.01 versus 0.36+/-0.03 pools per day, respectively; P<0.001) and a significant increase in the production rate [20.7+/-4.4 versus 14. 0+/-2.4 mg. kg-1. d-1, respectively; P<0.01] of LDL apoB in the probands compared with normolipidemic controls. We then studied the in vivo biodistribution and tissue uptake of 99mtechnetium-labeled LDL in the probands and compared them with those in normal controls and 1 FH homozygote. The probands showed a significant reduction in hepatic LDL uptake, similar to that observed in the FH homozygote. A reduced uptake of LDL by the kidney and spleen was also observed in all patients. Our findings suggest that this recessive form of hypercholesterolemia is due to a marked reduction of in vivo LDL catabolism. This appears to be caused by a selective reduction in hepatic LDL uptake. We propose that in this new lipid disorder, a recessive defect causes a selective impairment of LDL receptor function in the liver.

Induction of Low-Density Lipoprotein Catabolism in Hep G2 Cells by a Fungal Sesquiterpene Ester, FR111142

A search for agents that can enhance low density lipoprotein (LDL) catabolism in Hep G2 cells has led to the identification of a fungal sesquiterpene ester, FR111142, as an active compound. The treatment of Hep G2 cells with 40 μM FR111142 at 37°C for 18 h caused a 1.9- to 2.2-fold elevation of binding, internalization and degradation of125I-LDL in the cells. The Scatchard analysis of the specific125I-LDL binding demonstrated that the agent caused an increase in the maximum LDL binding along with a slight decrease in the apparent dissociation constant value. The effect of FR111142 was not seen in cells treated by the agent for shorter periods or in cycloheximide-treated cells, suggesting that the effect involves an induction of LDL binding sites. Unlike 3-hydroxy-3-methyglutaryl CoA reductase inhibitors, FR111142 affected neither cholesterol synthesis nor the level of LDL receptor in Hep G2 cells. These results suggest that FR111142 enhances LDL catabolism in Hep G2 cells by a mechanism that involves a receptor other than LDL receptor.

Delayed Low Density Lipoprotein (LDL) Catabolism Despite a Functional Intact LDL-Apolipoprotein B Particle and LDL-Receptor in a Subject with Clinical Homozygous Familial Hypercholesterolemia

We identified a 38-yr-old male patient with the clinical expression of homozygous familial hypercholesterolemia presenting as severe coronary artery disease, tendon and skin xanthomas, arcus lipoides, and joint pain. The genetic trait seems to be autosomal recessive. Interestingly, serum concentrations of cholesterol responded well to diet and statins. We had no evidence of an abnormal low density lipoprotein (LDL)-apolipoprotein B (apoB) particle, which was isolated from the patient using the U937 proliferation assay as a functional test of the LDL-binding capacity. The apoB 3500 and apoB 3531 defects were ruled out by PCR. In addition, we found no evidence for a defect within the LDL-receptor by skin fibroblast analysis, linkage analysis, single-strand conformational polymorphism and Southern blot screening across the entire LDL-receptor gene. The in vivo kinetics of radioiodinated LDL-apoB were evaluated in the proband and three normal controls, subsequently. The LDL-apoB isolated from the patient showed a normal catabolism, confirming an intact LDL particle. In contrast the fractional catabolic rate (d−1) of autologous LDL in the subject and the normal controls revealed a remarkable delayed catabolism of the patient’s LDL (0.15 vs. 0.33–0.43 d−1). In addition, the elevation of LDL-cholesterol in the patient resulted from an increased production rate with 22.8 mg/kg per day vs. 12.7–15.7 mg/kg per day. These data indicate that there is another catabolic defect beyond the apoB and LDL-receptor gene causing familial hypercholesterolemia.

Increased VLDL in nephrotic patients results from a decreased catabolism while increased LDL results from increased synthesis

Increased VLDL in nephrotic patients results from a decreased catabolism while increased LDL results from increased synthesis

Additive inhibitory effect of hydrocortisone and cyclosporine on low-density lipoprotein receptor activity in cultured HepG2 cells

Both glucocorticoids and cyclosporine are used to prevent rejection in organ transplant recipients. However, long-term treatment with these drugs is known to induce hyperlipidemia and premature development of atherosclerosis. In previous studies, we have shown that the immunosuppressive drug cyclosporine inhibits catabolism of low-density lipoproteins (LDL) mainly by reducing the expression of LDL-receptor messenger RNA (mRNA), thus explaining the increased plasma levels of LDL cholesterol observed in patients treated with cyclosporine. In the present study, our objective was to investigate the mechanism by which glucocorticoids increase plasma levels of LDL cholesterol. We studied the catabolism of LDL in the human hepatoma cell line HepG2. Our results show that hydrocortisone at physiologically relevant concentrations inhibits LDL binding, uptake, and degradation in a dose-dependent way. Moreover, hydrocortisone also reduces the expression of LDL-receptor mRNA in a dose-dependent way. Cyclosporine also has an additive inhibitory effect on hydrocortisone in the catabolism of LDL. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor fluvastatin reverses the inhibitory effect of both hydrocortisone and cyclosporine. We conclude that treatment with hydrocortisone and/or cyclosporine induces increased plasma levels of LDL cholesterol because of reduced hepatic LDL receptor activity. HMG-CoA reductase inhibitors reverse this undesirable effect and thus reduce the risk of the development of atherosclerosis in patients subjected to immunosuppressive treatment. (Hepatology 1997 Oct;26(4):967-71)

Additive inhibitory effect of hydrocortisone and cyclosporine on low-density lipoprotein receptor activity in cultured HepG2 cells.

Both glucocorticoids and cyclosporine are used to prevent rejection in organ transplant recipients. However, long-term treatment with these drugs is known to induce hyperlipidemia and premature development of atherosclerosis. In previous studies, we have shown that the immunosuppressive drug cyclosporine inhibits catabolism of low-density lipoproteins (LDL) mainly by reducing the expression of LDL-receptor messenger RNA (mRNA), thus explaining the increased plasma levels of LDL cholesterol observed in patients treated with cyclosporine. In the present study, our objective was to investigate the mechanism by which glucocorticoids increase plasma levels of LDL cholesterol. We studied the catabolism of LDL in the human hepatoma cell line HepG2. Our results show that hydrocortisone at physiologically relevant concentrations inhibits LDL binding, uptake, and degradation in a dose-dependent way. Moreover, hydrocortisone also reduces the expression of LDL-receptor mRNA in a dose-dependent way. Cyclosporine also has an additive inhibitory effect on hydrocortisone in the catabolism of LDL. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor fluvastatin reverses the inhibitory effect of both hydrocortisone and cyclosporine. We conclude that treatment with hydrocortisone and/or cyclosporine induces increased plasma levels of LDL cholesterol because of reduced hepatic LDL receptor activity. HMG-CoA reductase inhibitors reverse this undesirable effect and thus reduce the risk of the development of atherosclerosis in patients subjected to immunosuppressive treatment.