Influence of HDL-cholesterol-elevating drugs on the in vitro activity of the HDL receptor SR-BI

Treatment of atherosclerotic disease often focuses on reducing plasma LDL-cholesterol or increasing plasma HDL-cholesterol. We examined in vitro the effects on HDL receptor [scavenger receptor class B type I (SR-BI)] activity of three classes of clinical and experimental plasma HDL-cholesterol-elevating compounds: niacin, fibrates, and HDL376. Fenofibrate (FF) and HDL376 were potent (IC(50) approximately 1 microM), direct inhibitors of SR-BI-mediated lipid transport in cells and in liposomes reconstituted with purified SR-BI. FF, a prodrug, was a more potent inhibitor of SR-BI than an activator of peroxisome proliferator-activated receptor alpha, a target of its active fenofibric acid (FFA) derivative. Nevertheless, FFA, four other fibrates (clofibrate, gemfibrozil, ciprofibrate, and bezafibrate), and niacin had little, if any, effect on SR-BI, suggesting that they do not directly target SR-BI in vivo. However, similarities of HDL376 treatment and SR-BI gene knockout on HDL metabolism in vivo (increased HDL-cholesterol and HDL particle sizes) and structure-activity relationship analysis suggest that SR-BI may be a target of HDL376 in vivo. HDL376 and other inhibitors may help elucidate SR-BI function in diverse mammalian models and determine the therapeutic potential of SR-BI-directed pharmaceuticals.     

Subchronic exposure to high-dose ACE-inhibitor moexipril induces catalase activity in rat liver

The long-term clinical effects of ACE-inhibitors have similarities with those of both fibrates and glitazones, activators of peroxisome proliferator activator receptor (PPAR) alpha and gamma, respectively. The antioxidant enzyme catalase, a heme protein that degrades hydrogen peroxide, is found at high concentrations in peroxisomes. Catalase activity is one of the recognized surrogate markers indicative of PPAR activation in the rat liver. The purpose of the study was to establish the effect of moexipril on catalase activity and to compare it with the effect of both saline controls and that of the known PPAR agonist clofibrate (positive control). Three groups of seven rats were used. All substances were applied i.p. daily for 5 days, followed by a 2-day break. The cycle was repeated eight times. After the final cycle (day 56) the animals were sacrificed and liver tissue collected. The number of catalase positive cells in both moexipril group (95% CI 57–61) and clofibrate group (95% CI 72–80) is higher than in controls (95% CI 3–16) (p ≤ 0.01). The number of catalase positive cells in the clofibrate group is higher than in the moexipril group (p ≤ 0.01). High-dose subchronic exposure to the ACE-inhibitor moexipril induces catalase activity in the rat liver to an extent comparable to fibrates. We suggest that some of the long-term advantages of ACE inhibitor use – beyond mere BP lowering – might be due to a PPAR mediated effect. (Mol Cell Biochem xxx: 159–163, 2005)     

Fenofibrate: a novel formulation (Triglide) in the treatment of lipid disorders: a review

Cardiovascular disease is the major cause of mortality worldwide and accounts for approximately 40% of all deaths. Dyslipidemia is one of the primary causes of atherosclerosis and effective interventions to correct dyslipidemia should form an integral component of any strategy aimed at preventing cardiovascular disease. Fibrates have played a major role in the treatment of hyperlipidemia for more than two decades. Fenofibrate is one of the most commonly used fibrates worldwide. Since fenofibrate was first introduced in clinical practice, a major drawback has been its low bioavailability when taken under fasting conditions. Insoluble Drug Delivery-Microparticle fenofibrate is a new formulation that has an equivalent extent of absorption under fed or fasting conditions. In this review, we will discuss the clinical pharmacology of fenofibrate, with particular emphasis on this novel formulation, as well as its lipid-modulating and pleiotropic actions. We will also analyze the major trial that evaluated fibrates for primary and secondary prevention of cardiovascular disease, the safety and efficacy profile of fibrate-statin combination treatment, and the current recommendations regarding the use of fibrates in clinical practice.     

VAP II analysis of lipoprotein subclasses in mixed hyperlipidemic patients on treatment with ezetimibe/simvastatin and fenofibrate

This analysis evaluates the effects on lipoprotein subfractions and LDL particle size of ezetimibe/simvastatin with or without coadministration of fenofibrate in patients with mixed hyperlipidemia. This multicenter, double-blind, placebo-controlled, parallel-group study included 611 patients aged 18-79 years randomized in 1:3:3:3 ratios to one of four 12 week treatment groups: placebo; ezetimibe/simvastatin 10/20 mg/day; fenofibrate 160 mg/day; or ezetimibe/simvastatin 10/20 mg/day + fenofibrate 160 mg/day. At baseline and study endpoint, cholesterol associated with VLDL, intermediate density lipoprotein (IDL), LDL, and HDL subfractions was quantified using the Vertical Auto Profile II method. LDL particle size was determined using segmented gradient gel electrophoresis. Whereas fenofibrate reduced cholesterol mass within VLDL and IDL, and shifted cholesterol from dense LDL subfractions into the more buoyant subfractions and HDL, ezetimibe/simvastatin reduced cholesterol mass within all apolipoprotein B-containing particles without significantly shifting the LDL particle distribution profile. When administered in combination, the effects of the drugs were complementary, with more-pronounced reductions in VLDL, IDL, and LDL, preferential loss of more-dense LDL subfractions, and increased HDL, although the effects on most lipoprotein subfractions were not additive. Thus, ezetimibe/simvastatin + fenofibrate produced favorable effects on atherogenic lipoprotein subclasses in patients with mixed hyperlipidemia.     

Hypertriglyceridemia Increases Mitochondrial Resting Respiration and Susceptibility to Permeability Transition

High plasma level of triglycerides (TGs) is a common feature in atherosclerosis, obesity, diabetes, alcoholism, stress, and infection. Since mitochondria have been implicated in cell death under a variety of metabolic disorders, we examined liver mitochondrial functions in hypertriglyceridemic transgenic mice. Hypertriglyceridemia increased resting respiration and predisposed to mitochondrial permeability transition (MPT). Ciprofibrate therapy reduced plasma TG levels, normalized respiration, and prevented MPT. The higher resting respiration in transgenic mitochondria remained in the presence of the adenine nucleotide carrier inhibitor, carboxyatractyloside, bovine serum albumin, and the uncoupling proteins (UCPs) inhibitor, GDP. UCP2 content was similar in both control and transgenic mitochondria. We propose that faster resting respiration represents a regulated adaptation to oxidize excess free fatty acid in the transgenic mice.     

Immunohistochemical assessment of proliferating cell nuclear antigen in primary hepatocellular carcinoma and dysplastic nodules

A complementary way for the assessment of HCC prognosis is represented by the analysis of molecular markers. Thus, immunohistochemical assessment of proliferation can describe tumor aggressiveness, probability of local recurrence or metastasis potential, being very useful for the assessment of recurrence-free survival and survival until death. The aim of our study was to assess proliferating cell nuclear antigen activity in HCC and dysplastic nodules as compared with surrounding nonneoplasic areas. Immunohistochemical techniques were thus performed on the samples obtained by ultrasound-guided liver biopsies or intraoperative biopsies, in 32 patients with HCC, as well as in 3 patients with dysplastic nodules ocurring in liver cirrhosis. Expression of PCNA within extranodular areas of the HCC patients in the absence or presence of cirrhosis, was increasing from 40% to 70%, respectively. PCNA expression further increased within intranodular areas of dysplastic nodules and HCC, to 100% and 96.88%, respectively. A progressive increase of the mean values of PCNA-LI was also observed from extranodular areas without or with cirrhosis, towards intranodular areas of dysplastic nodules and HCC (4.2%, 6.8%, 31.9%, respectively). Dysplastic nodules can thus be considered lesions with a high-proliferation rate, representing an early stage of hepatocarcinogenesis. This supported the current recommendations for borderline hepatocellular nodules identified by ultrasound, which indicate an aggressive treatment similar to malignant lesions. In summary, we demonstrated a progressively increasing rate of cellular proliferation, from extranodular non-neoplasic areas to intranodular areas (dysplastic nodules and HCC), as reflected by an increased expression of proliferating cell nuclear antigen labelling index.     

Genetic-dependency of peroxisomal cell functions - emerging aspects

This paper reviews aspects concerning the genetic regulation of the expression of the well studied peroxisomal genes including those of fatty acid β-oxidation enzymes; acyl-CoA oxidase, multifunctional enzyme and thiolase from different tissues and species. An important statement is PPARα, which is now long known to be in rodents the key nuclear receptor orchestrating liver peroxisome proliferation and enhanced peroxisomal β-oxidation, does not appear to control so strongly in man the expression of genes involved in peroxisomal fatty acid β-oxidation related enzymes. In this respect, the present review strengthens among others the emerging concept that, in the humans, the main genes whose expression is up-regulated by PPARα are mitochondrial and less peroxisomal genes. A special emphasis is also made on the animal cold adaptation and on need for sustained study of peroxisomal enzymes and genes; challenging that some essential roles of peroxisomes in cell function and regulation still remain to be discovered.     

Glycogen Synthase Kinase-3α Promotes Fatty Acid Uptake and Lipotoxic Cardiomyopathy

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Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levels

Over the past several years, proprotein convertase subtilisin kexin type 9 (PCSK9) has gained significant attention as a key regulator of serum LDL-cholesterol (LDL-C) levels. In humans, gain-of-function mutations in PCSK9 cause a form of familial hypercholesterolemia, whereas loss-of-function mutations result in significantly decreased LDL-C and cardiovascular risk. Our laboratory was the first to demonstrate that atorvastatin increases PCSK9 serum levels, an observation that has since been confirmed by at least two other groups. In light of these observations, we studied the effect of another common lipid-lowering medication, fenofibrate, on circulating PCSK9 protein levels in patients treated with fenofibrate or placebo for 12 weeks. We observed that fenofibrate (200 mg per day) significantly increased circulating PCSK9 levels by 25% compared with baseline. Placebo treatment, in comparison, had no effect on PCSK9 levels. Interestingly, fenofibrate-induced increases in serum PCSK9 levels were highly correlated with fenofibrate-induced changes in HDL-C and triglyceride levels, as well as with fenofibrate-induced changes in LDL-C levels. These results suggest an explanation for why fibrates do not achieve as much LDL-C lowering as might otherwise be expected and indicate that the addition of a PCSK9 inhibitor to fibrate therapy may result in additional beneficial LDL-C lowering.