Albumin inhibits apolipoprotein AI and AII production in human hepatoblastoma cell line (Hep G2): additive effects of oleate-albumin complex

Although the role of multiple humoral agents (such as plasma albumin, glucose, hormones etc.) are implicated in lipoprotein metabolism, the mechanism of action of these agents on various steps of the synthesis and secretion of lipoproteins and apolipoproteins (protein moieties of lipoproteins) are not completely understood. Specifically, the hepatocellular mechanisms of the effect of albumin and fatty acids on apolipoprotein (apo) AI and AII [major proteins of high density lipoproteins (HDL)] synthesis and secretion are not known. Using human hepatoblastoma cells (Hep G2) as an in vitro model system, this study examined the effect of albumin and fatty acids on the synthesis, secretion, and the steady-state mRNA expression of apo AI and AII. The data indicated that the incubation of Hep G2 cells with albumin, dose-dependently, inhibited apo AI and AII accumulation (secretion) in the media, de novo synthesis, and the steady-state mRNA expression. Albumin did not alter total protein synthesis; thus the effect of albumin appeared to be specific for the synthesis and secretion of apo AI and apo AII. Free fatty acids (FFA) are transported by albumin and diseases characterized by enhanced FFA mobilization (e.g. diabetes mellitus) are associated with low HDL levels. Studies were therefore performed to examine the effect of albumin-bound-oleic acid on apo AI and apo AII production. The results showed that the albumin-oleate complex further increased the inhibitory effects of albumin on apo AI and apo AII production. These data suggest how HDL metabolism may be affected at the hepatocellular level by alterations in plasma albumin concentrations and/or fatty acid mobilization in clinical situations characterized by altered HDL levels.     

Mechanism of action of niacin on lipoprotein metabolism

It is generally accepted that the increased concentrations of apolipoprotein (apo) B containing very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL), and decreased levels of apo AI containing high-density lipoproteins (HDL) are correlated to atherosclerotic cardiovascular disease. Current evidence indicates that the post-translational apo-B degradative processes regulate the hepatic assembly and secretion of VLDL and the subsequent generation of LDL particles. The availability of triglycerides (TG) for the addition to apo B during intracellular processing appears to play a central role in targeting apo B for either intracellular degradation or assembly and secretion as VLDL particles. Based on the availability of TG, the liver secretes either dense TG-poor VLDL2 or large TG-rich VLDL1 particles, and these particles serve as precursors for the formation of more buoyant or small, dense LDL particles by lipid transfer protein- and hepatic lipase-mediated processes. HDLs are a heterogenous class of lipoproteins, and apo AI (the major protein of HDL) participates in reverse cholesterol transport, a process by which excess cholesterol is eliminated. Recent studies indicate that HDL particles containing only apo A-I (LPA-I) are more effective in reverse cholesterol transport and more anti-atherogenic than HDL particles containing both apo A-I and apo A-II (LPA-I+A-II).     

Niacin: An old drug rejuvenated

Niacin has long been used in the treatment of dyslipidemia and cardiovascular disease. Recent research on niacin has been focused on understanding the mechanism of action of niacin and preparation of safer niacin formulations. New findings indicate that niacin does the following: 1) it inhibits hepatic diacylglycerol acyltransferase 2, resulting in inhibition of triglyceride synthesis and decreased apolipoprotein B-containing lipoproteins; 2) it decreases the surface expression of hepatic adenosine triphosphate synthase β-chain, leading to decreased holoparticle high-density lipoprotein catabolism and increased high-density lipoprotein levels; and 3) it increases redox potential in arterial endothelial cells, resulting in inhibition of redox-sensitive genes. Flushing, an adverse effect of niacin, results from niacin receptor GPR109A-mediated production of prostaglandin D2 and E2 via DP1 and EP2/4 receptors. DP1 receptor antagonist (laropiprant) attenuates the niacin flush. A reformulated preparation of extended-release niacin (Niaspan; Abbott, Abbott Park, IL) lowers flushing compared with an older Niaspan formulation. These advancements in niacin research have rejuvenated its use for the treatment of dyslipidemia and cardiovascular disease.     

Synthesis of some new indolo[2,3-c]isoquinolinyl pyrazoles, -1,3,4-oxadiazoles and their biological activities

A new series of novel compounds [10-substituted 6H, 7H-indolo[2,3-c]isoquinolin-5-one-6-yl]carbohydrazides (3a–c), 1-[10-substituted 6H, 7H-indolo[2,3-c]isoquinolin-5-one-6-yl]fomyl-, -3′,5′-dimethylpyrazoles (4a–c), -3′,5′-diphenylpyrazoles (5a–c), -3′-methylpyrazol-5′-ones (6a–c) and -1′,3′,4′-oxidiazole-2′-thiones (7a–c) linked to indoloisoquinoline at position-6 through formyl bridge was prepared. The structures of these newly synthesized compounds were confirmed by their spectral studies and elemental analysis. These compounds have been screened for their antimicrobial and antioxidant activities. Compounds 4a, 4b, 5a, 5b, 5c, 6b, 7a, and 7c exhibited the maximum zone of inhibition against A. niger, A. flavus, and A. fumigatus. Compounds 4a, 5a, 5c, 6b, 6c, 7a, and 7b showed good antibacterial activity. Compounds 4b, 4c, 5b, 5c, 6a, 6b, 7a, 7b, and 7c showed good radical scavenging activity compared with standards.     

The mechanism and mitigation of niacin‐induced flushing

Aims:  To summarise the metabolic responses to niacin that can lead to flushing and to critically evaluate flushing mitigation research. Methods and results:  This comprehensive review of the mechanism of action of niacin‐induced flushing critically evaluates research regarding flushing mitigating formulations and agents. Niacin induces flushing through dermal Langerhans cells where the activation of G protein‐coupled receptor 109A (GPR109A) increases arachidonic acid and prostaglandins, such as prostaglandin D₂ (PGD₂) and prostaglandin E₂ (PGE₂), subsequently activating prostaglandin D₂ receptor (DP₁), prostaglandin E₂ receptor (EP₂) and prostaglandin E receptor 4 (EP₄) in capillaries and causing cutaneous vasodilatation. Controlling niacin absorption rates, inhibiting prostaglandin production, or blocking DP₁, EP₂ and EP₄ receptors can inhibit flushing. Niacin extended‐release (NER) formulations have reduced flushing incidence, duration and severity relative to crystalline immediate‐release niacin with similar lipid efficacy. Non‐steroidal anti‐inflammatory drugs (NSAIDs), notably aspirin given 30 min before NER at bedtime, further reduce flushing. An antagonist to the DP₁ receptor (laropiprant) combined with an ER niacin formulation can reduce flushing; however, significant residual flushing occurs with clinically‐relevant dosages. Conclusions:  Niacin is an attractive option for treating dyslipidemic patients, and tolerance to niacin‐induced flushing develops rapidly. Healthcare professionals should particularly address flushing during niacin dose titration.     

Oxidized low-density lipoprotein stimulates monocyte adhesion to glomerular endothelial cells.

BACKGROUND: Abnormalities in lipid and lipoprotein metabolism have been implicated in the pathogenesis of glomerulosclerosis. Atherogenic lipoproteins [for example, low-density lipoprotein (LDL) and oxidized LDL (ox-LDL)] have been shown to stimulate glomerular monocyte chemoattractants involved in monocyte infiltration. However, the role of LDL and ox-LDL in the early monocyte adhesion to glomerular endothelial cells (ECs) and associated intracellular signaling mechanisms are not clearly understood. METHODS: In this study, we examined the effect of LDL and ox-LDL on intracellular signaling mechanisms associated with monocyte adhesion to glomerular ECs and intercellular adhesion molecule-1 (ICAM-1) expression. RESULTS: Ox-LDL, but not LDL, stimulated EC ICAM-1 expression and monocyte adhesion. Ox-LDL elevated protein tyrosine kinase (PTK) activity, and the preincubation of ECs with specific PTK inhibitors blocked ox-LDL-induced ICAM-1 message and monocyte adhesion. Whereas experimental maneuvers that inhibit either protein kinase C activation (by PKC depletion or with inhibitors) or Gi-protein-mediated pathways (pertussis toxin sensitive) had no effect on ox-LDL-induced monocyte adhesion and ICAM-1 expression. cAMP-elevating compounds did not induce ICAM-1 or monocyte adhesion. CONCLUSIONS: The data indicate that ox-LDL, by stimulating monocyte adhesion to the glomerular endothelium, may regulate monocyte infiltration within the glomerulus, supporting an early pathobiological role for atherogenic lipoproteins in glomerular injury. The results suggest that the activation of specific PTK and associated signaling may, at least in part, play a critical role in ox-LDL-mediated endothelial-monocyte interaction-related events. The data suggest that the interventions aimed at modifying associated intracellular signaling events within the glomerulus may provide potential therapeutic modalities in monocyte/macrophage-mediated glomerular disease.     

In vivo and in vitro peroxisome proliferation properties of selected clofibrate analogues in the rat. Structure-activity relationships

We have examined, relative to clofibric acid (CPIB), the effects of a chemical series of phenoxyacetic acids and of two asymmetric CPIB analogues, the R(+)- and S(-)-enantiomers of 2-(4-chlorophenoxy)propionic acid (4-CPPA) and 2-(4-chlorophenoxy)butyric acid (4-CPBA), on hepatic peroxisome proliferation both in vivo and in vitro utilizing cholesterol-fed rats and primary cultured rat hepatocytes respectively. Peroxisome proliferation was assessed by measuring changes in peroxisomal fatty acyl-CoA oxidase (FACO) and microsomal laurate hydroxylase (LH) activities as well as by electron microscopic examination of 3,3'-diaminobenzidine-stained liver slices. CPIB and enantiomers of 4-CPPA and 4-CPBA (0.6 mmol/kg/day for 7 days) produced hepatomegaly, lowered serum cholesterol levels, and caused 4.7- to 12.9-fold and 2.9- to 6.1-fold increases in hepatic FACO and LH activities, respectively, in cholesterol-fed rats. Electron micrographs of liver cells showed an increased number of peroxisomes from cholesterol-fed rats given S(-)-4-CPBA and CPIB. Likewise, these compounds (0.03 to 1.0 mM) induced FACO and LH in primary rat hepatocyte cultures after 72 hr. R(+)- and S(-)-Enantiomers of 4-CPPA produced similar concentration-dependent and maximal increases in both FACO and LH activities, whereas enantiomeric selectivity [S(-) greater than R(+)] for the induction of these two enzymes was observed with the isomers of 4-CPBA. The increases in the activities of FACO and LH caused by S(-)-4-CPBA were similar to those elicited by 1.0 mM CPIB (58.6- and 9.8-fold respectively). These results show that the enantiomers of 4-CPPA and 4-CPBA induce the peroxisome proliferation-associated enzymes FACO and LH in vivo and in vitro, and that the S(-)-isomer of 4-CPBA causes a greater induction of FACO and LH in vitro than its corresponding R(+)-isomer, indicating that these two enzymes are induced in an enantioselective manner. Optimal induction of the peroxisome proliferation-associated enzymes FACO and LH in rat hepatocyte cultures was produced by phenoxyacetic acids possessing (1) a chlorine atom at the 4-position of the phenyl ring, (2) a dimethyl or mono-ethyl substitution at the alpha-carbon atom of the carboxylic acid side chain; and (3) an S(-)-orientation for chiral analogues possessing a mono-ethyl group at the alpha-carbon atom of the carboxylic acid side chain.(ABSTRACT TRUNCATED AT 400 WORDS)