The Critical Role of the Branched Chain Amino Acids (BCAAs) Catabolism-Regulating Enzymes, Branched-Chain Aminotransferase (BCAT) and Branched-Chain α-Keto Acid Dehydrogenase (BCKD), in Human Pathophysiology.

Branched chain amino acids (BCAAs), leucine, isoleucine and valine, are essential amino acids widely studied for their crucial role in the regulation of protein synthesis mainly through the activation of the mTOR signaling pathway and their emerging recognition as players in the regulation of various physiological and metabolic processes, such as glucose homeostasis. BCAA supplementation is primarily used as a beneficial nutritional intervention in chronic liver and kidney disease as well as in muscle wasting disorders. However, downregulated/upregulated plasma BCAAs and their defective catabolism in various tissues, mainly due to altered enzymatic activity of the first two enzymes in their catabolic pathway, BCAA aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKD), have been investigated in many nutritional and disease states. The current review focused on the underlying mechanisms of altered BCAA catabolism and its contribution to the pathogenesis of a numerous pathological conditions such as diabetes, heart failure and cancer. In addition, we summarize findings that indicate that the recovery of the dysregulated BCAA catabolism may be associated with an improved outcome and the prevention of serious disease complications.

No effect of fenugreek, bergamot and olive leaf extract on glucose homeostasis in patients with prediabetes: a randomized double-blind placebo-controlled study.

INTRODUCTION: The main pathophysiologic mechanism of type 2 diabetes (T2D) is insulin resistance, which exists several years before T2D diagnosis. The term 'prediabetes' applies to patients with insulin resistance but without overt T2D. The improvement of glucose homeostasis in these patients may prevent or delay the development of T2D and its complications. Data suggest that fenugreek, olive leaf polyphenols and bergamot extract may improve carbohydrate metabolism. We examined the effect of an agent containing fenugreek, olive leaf polyphenols and bergamot extract (active agent) on glucose homeostasis in patients with prediabetes. MATERIAL AND METHODS: This was a single-center, randomized, double-blind, placebo-controlled trial; patients with prediabetes (N = 100) were randomized to treatment with the active agent or placebo. The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) at 6 months after treatment initiation. Secondary endpoints included changes in other parameters of glucose metabolism and lipid profile. RESULTS: Overall 87 patients completed the study. No significant change in HbA1c was observed in either treatment group. Similarly, fasting plasma glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR) index and lipid profile remained unaltered in both groups. CONCLUSIONS: The administration of an agent containing fenugreek, olive leaf polyphenols and bergamot extract for 6 months did not improve glycemia or lipid parameters in patients with prediabetes.

Sitosterolemia: A multifaceted metabolic disorder with important clinical consequences.

Sitosterolemia is a metabolic disorder characterized by increased intestinal absorption and tissue accumulation of phytosterols. Although sitosterolemia is considered a rare disease, its prevalence may be significantly higher than initially thought. Indeed, accumulating evidence suggests that patients with unexplained hematologic abnormalities or premature cardiovascular disease in the absence of classic risk factors may exhibit disordered phytosterol metabolism. In this review, we present a patient with sitosterolemia, describe the pathophysiology and the clinical picture of this disorder, and discuss the clinical value of phytosterol supplementation in patients with primary dyslipidemias.

Effect of Plant Polyphenols on Adipokine Secretion from Human SGBS Adipocytes.

Introduction. Adipose tissue contributes to atherosclerosis with mechanisms related to adipokine secretion. Polyphenols may exhibit antiatherogenic properties. The aim of the study was to investigate the effects of three polyphenols, namely, quercetin, epigallocatechin gallate (EGCG), and resveratrol on adipokine secretion from cultured human adipocytes. Methods. Human SGBS adipocytes were treated with quercetin, EGCG, and resveratrol for 24 and 48 hours. Visfatin, leptin, and adiponectin were measured in the supernatant. Results. Visfatin secretion was inhibited by quercetin 10 µM by 16% and 24% at 24 and 48 hours respectively. The corresponding changes for quercetin 25 µM were 47% and 48%. Resveratrol 25 µM reduced visfatin by 28% and 38% at 24 and 48 hours. EGCG did not have an effect on visfatin. None of tested polyphenols influenced leptin and adiponectin secretion. Conclusion. Quercetin and resveratrol significantly decreased visfatin secretion from SGBS adipocytes. This effect may contribute to their overall antiatherogenic properties.

Salicylate-induced proximal tubular dysfunction.

We describe the case of a 17-year-old girl who was admitted to our clinic for drug poisoning. Twelve hours after the ingestion of 25 tablets of aspirin (12.5 g of acetylsalicylic acid), the patient had a generalized proximal tubular dysfunction characterized by glucosuria (in the face of normal serum glucose levels), proteinuria, and uric acid wasting. Further characterization of the tubular dysfunction using high-resolution proton nuclear magnetic resonance spectroscopy of the urine showed a pattern consistent with proximal tubular injury. An important characteristic of the salicylate-induced proximal tubular dysfunction in our patient was its rapid reversibility. A trend toward normalization of fractional excretion values of electrolytes was observed 2 days after ingestion. Determination of serum and urine metabolites and spectroscopy of urine 15 days later showed no evidence of tubular dysfunction. The mechanisms potentially implicated in the pathogenesis of salicylate-induced Fanconi syndrome are discussed and a brief review of the relevant literature is provided.

Disturbances of phosphate metabolism: another feature of metabolic syndrome.

BACKGROUND: Despite important recent advances in the understanding of the consequences of metabolic syndrome, its pathophysiological characteristics remain unclear. It has been proposed that disturbances in phosphate metabolism may contribute to the development of this constellation of cardiovascular risk factors. However, there have been insufficient clinical data supporting this hypothesis to date. The aim of our study is to confirm the presence of hypophosphatemia in patients with metabolic syndrome, as well as investigate mechanisms that may underlie the disturbances in phosphate metabolism in this patient group. METHODS: Two hundred fifty-five individuals were enrolled. The diagnosis of metabolic syndrome was based on Adult Treatment Panel III guidelines. Subjects with fewer than 3 criteria served as controls. RESULTS: Patients with metabolic syndrome showed significantly lower phosphate and magnesium levels compared with controls. Because fractional excretion of phosphate was similar in both groups, we assume that hypophosphatemia in patients with metabolic syndrome can be attributed to decreased dietary intake, as well as internal redistribution of this element. Lower magnesium values in the patient group may result from the same mechanisms as lower phosphate levels. In addition, hyperinsulinemia-induced renal magnesium wasting also may be a contributory factor. CONCLUSION: Patients with metabolic syndrome show significantly lower phosphate and magnesium levels compared with healthy individuals. The clinical significance of these disturbances, as well as their importance as targets for preventive or therapeutic interventions, remains to be established.

The PON1 M55L gene polymorphism is associated with reduced HDL-associated PAF-AH activity.

The platelet-activating factor acetylhydrolase activity associated with high density lipoprotein (HDL-PAF-AH) may substantially contribute to the antioxidant, anti-inflammatory, and overall antiatherogenic effects of HDL. Two enzymes associated with HDL express PAF-AH catalytic activity, PAF-AH itself and paraoxonase-1 (PON1). The relative contribution of these enzymes in the expression of PAF-AH activity on HDL remains to be established. We investigated whether the PON1 polymorphisms (M55L and Q192R) or the PAF-AH polymorphism V379A could affect the PAF-AH activity associated with HDL in both normolipidemic and dyslipidemic (type IIA and IIB) populations. We show for the first time that the PON1 M55L polymorphism significantly affects the HDL-PAF-AH activity in all studied groups, the PON1 L55L individuals having lower enzyme activity compared to those having 1 M and 2 M alleles. No differences in the HDL content concerning the major apolipoprotein and lipid constituents were observed between individuals carrying the PON1 L55L and those with the M55M polymorphism. Our results provide evidence that PON1 significantly contributes to the pool of HDL-PAF-AH activity in human plasma, and suggest that the low PAF-AH activity in HDL carrying the PON1 L alloenzyme may be an important factor contributing to the low efficiency of this HDL in protecting LDL against lipid peroxidation.

Altered distribution of platelet-activating factor- acetylhydrolase activity between LDL and HDL as a function of the severity of hypercholesterolemia.

Platelet-activating factor-acetylhydrolase (PAF-AH) is a lipoprotein-associated phospholipase A2 capable of hydrolyzing platelet-activating factor (PAF) and oxidatively modified phospholipids. We studied the plasma- and lipoprotein-associated PAF-AH activity in patients with primary hypercholesterolemia. Thirty-eight unrelated patients with heterozygous familial hypercholesterolemia (HeteroFH), five patients with homozygous FH (HomoFH), and 33 patients with primary non-FH hypercholesterolemia (NonFH) participated in the study. In all patient groups the plasma PAF-AH activity was significantly elevated compared with 33 normolipidemic controls, the HomoFH having the highest and the NonFH patients showing the lowest enzyme activity. Gradient ultracentrifugation studies showed that this increase is not only due to the elevation in the plasma LDL but also to the increase in the PAF-AH activity associated with each LDL subfraction, being more profound in the small-dense LDL-5. Unlike LDL, no difference in the HDL-associated PAF-AH activity was observed among all groups. Consequently, an altered distribution of enzyme activity among apolipoprotein B (apoB)- and apolipoprotein A-I (apoA-I)-containing lipoproteins is observed in hypercholesterolemic patients, resulting in a significant decrease in the ratio of the HDL-associated PAF-AH to the total plasma enzyme activity compared with controls. This reduction is proportional to the increase of the plasma LDL-cholesterol (LDL-C) levels and consequently to the severity of the hypercholesterolemia. Thus, the ratio of HDL-associated PAF-AH-total plasma enzyme activity may be useful as a potential marker of atherogenicity in subjects with primary hypercholesterolemia.

Atorvastatin preferentially reduces LDL-associated platelet-activating factor acetylhydrolase activity in dyslipidemias of type IIA and type IIB.

Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is a phospholipase A(2) that is primarily associated with low density lipoprotein (LDL). PAF-AH activity has also been found in high density lipoprotein (HDL), although it has recently been indicated that there is no PAF-AH protein in HDL. Plasma paraoxonase 1 (PON1) is an HDL-associated esterase, which also exhibits PAF-AH-like activity. The effect of atorvastatin (20 mg per day for 4 months) on PAF-AH and PON1 activities in patients with dyslipidemia of type IIA (n=55) or type IIB (n=21) was studied. In both patient groups, atorvastatin significantly reduced plasma PAF-AH activity because of the decrease in LDL plasma levels and the preferential decrease in PAF-AH activity on dense LDL subfractions (LDL-4 and LDL-5). Drug therapy did not affect HDL-associated PAF-AH activity or serum PON1 activities toward paraoxon and phenylacetate in either patient group. However, because of the reduction in LDL cholesterol levels, the ratios of HDL-associated PAF-AH and serum PON1 activities to LDL cholesterol levels were significantly increased after drug administration. The reduction of the LDL-associated PAF-AH activity and the elevation in the ratios of HDL-associated PAF-AH and PON1 activities to LDL plasma levels may represent a new dimension in the antiatherogenic effect of atorvastatin.