The assembly of lipids into lipoproteins during secretion

Summary The process of assembly and secretion of lipoproteins is discussed with particular reference to the role of lipids. The majority of circulating lipoproteins is produced by the liver (80%) with the remainder being supplied by the intestine. The liver secretes both very low density lipoproteins and high density lipoproteins, but the assembly and secretion of these two types of particles may follow different routes. The major lipid components of lipoproteins are triacylglycerols, cholesterol, cholesterol esters and phospholipids. The biosynthesis of these lipids occurs on membranes of the endoplasmic reticulum, with many of the enzymes also being present in the Golgi; the roles of these two subcellular organelles in the assembly of lipoproteins are discussed. There appears to be a compartmentalization of lipids in cells, such that defined pools, often those newly-synthesized, are preferred, or even required, for lipoprotein assembly. The process of hepatic very low density lipoprotein secretion appears to be regulated by the supply of lipids. Indeed, the synthesis of new lipid may be a major driving force in lipoprotein assembly and secretion.     

Interaction of lipid transfer protein with plasma lipoproteins and cell membranes

Summary The hydrophobic lipid components of lipoproteins, cholesteryl ester and triglyceride, are transferred between all lipoproteins by a specific plasma glycoprotein, termed lipid transfer protein (LTP). LTP facilitates lipid transfer by an exchange process in which cholesteryl ester and triglyceride compete for transfer. Thus, LTP promotes remodeling of the lipoprotein structure, and plays an important role in the intravascular metabolism of these particles and in the lipoprotein-dependent pathways of cholesterol clearance from cells. The properties of LTP, its mechanisms of action, its roles in lipoprotein metabolism, and its modes of regulation are reviewed along with recent data that suggest a possible role for this protein in directly modifying cellular lipid composition.     

Cholesteryl ester transfer protein and its inhibition

Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesteryl esters from the atheroprotective high density lipoprotein (HDL) to the proatherogenic low density lipoprotein cholesterol (LDL) and very low density lipoprotein cholesterol (VLDL) leading to lower levels of HDL but raising the levels of proatherogenic LDL and VLDL. Inhibition of CETP is considered a potential approach to treat dyslipidemia. However, discussions regarding the role of CETP-mediated lipid transfer in the development of atherosclerosis and CETP inhibition as a potential strategy for prevention of atherosclerosis have been controversial. Although many animal studies support the hypothesis that inhibition of CETP activity may be beneficial, negative phase III studies on clinical endpoints with the CETP inhibitor torcetrapib challenged the future perspectives of CETP inhibitors as potential therapeutic agents. The review provides an update on current understanding of the molecular mechanisms involved in CETP activity and its inhibition.     

Changes in the lipoproteins of rabbits on a high-fat,cholesterol-free diet; preventive action of metformin

Summary Endogenous hypercholesterolemia induced by a cholesterol-free, high-fat diet corresponds to an increase in the level of low density lipoproteins and their enrichment in cholesterol esters. Metformin has no effect on the rise in plasma cholesterol but completely prevents the appearance of cholesterol-rich low-density lipoprotein.     

Effect of acetone on VLDL secretion by the isolated rat liver.

High acetone levels occur in uncontrolled diabetes and after isopropanol administration to rats. In both conditions, very low density lipoproteins (VLDL) secretion is depressed. Acetone, hoever, failed to affect the VLDL secretion rate by the isolated perfused rat liver, suggesting that this metabolite is not involved in impaired VLDL production in diabetes and after isopropanol administration.     

Effect of acetone on VLDL secretion by the isolated rat liver

Summary High acetone levels occur in uncontrolled diabetes and after isopropanol administration to rats. In both conditions, very low density lipoproteins (VLDL) secretion is depressed. Acetone, however, failed to affect the VLDL secretion rate by the isolated perfused rat liver, suggesting that this metabolite is not involved in impaired VLDL production in diabetes and after isopropanol administration.     

Lipoprotein lipase activator deficiency in very low density lipoproteins in rat nephrotic syndrome.

Marked urinary loss of lipoprotein lipase activator in experimental rat nephrotic syndrome may be partly responsible for its deficiency in plasma very low density lipoproteins.     

Lipid transport in the migrating Monarch butterfly,Danaus p. plexippus

Summary The transport of lipid in the haemolymph of the Monarch butterfly during its fall migration was examined. Diglyceride was the major lipid class of 2 electrophoretically distinct lipoprotein fractions in both males and females. Triglycerides, hydrocarbons, free fatty acids, phosphatidyl cholines and phosphatidyl ethanolamines were minor components of these lipoproteins. Differences in lipid transport attributable to sex were not detected.This study is a contribution of the Missouri Agricultural Experiment Station, Journal series No. 8520.     

Effect of Royal Jelly on serum lipids in experimental animals and humans with atherosclerosis

The primary objective of this review was to assess the size and consistency of Royal Jelly (RJ) effect on serum lipids in experimental animals and humans. The data from animal studies were pooled, where possible, and statistically evaluated by Student's t-test. Meta-analysis was used for the evaluation of human trials. It was found that RJ significantly decreased serum and liver total lipids and cholesterol levels in rats and rabbits and also retarded the formation of atheromas in the aorta of rabbits fed a hyperlipemic diet. Meta-analysis of the controlled human trials of RJ to reduce hyperlipidemia showed a significant reduction in total serum lipids and cholesterol levels and normalization of HDL and LDL as determined from decrease in β/α lipoproteins. The best available evidence suggests that RJ at approximately 50 to 100 mg per day, decreased total serum cholesterol levels by about 14%, and total serum lipids by about 10% in the group of patients studied.     

Hypolipidemic effects of garlic oil in rats fed ethanol and a high lipid diet

Summary Feeding of ethanol and a high fat-high cholesterol diet to rats markedly increased the total lipids in the liver, and cholesterol and triglyceride levels in the serum, liver and kidneys. However, when ethanol mixed with 0.5% garlic oil was fed to animals maintained on the high fat-high cholesterol diet, these lipid levels were significantly reduced to levels near to those seen in untreated control rats. Garlic oil did not reduce the serum albumin or the total proteins of liver, kidneys or serum when fed along with ethanol. Probably the garlic oil enhances the catabolism of dietary cholesterol and fatty acids.The authors acknowledge with thanks the financial assistance of the University of Maiduguri for carrying out this project.     

Studies on the late-pre-beta-lipoprotein of human serum.

Very low density lipoprotein (VLDL) isolated from 3 healthy normolipidaemic subjects had a raised VLDL cholesterol to triglyceride ratio. The VLDL fractions gave 2 pre-beta-bands on agarose gel electrophoresis. Family study of the subjects appears to indicate sex linkage of this trait and a possible polygenic type of inheritance.     

Apolipoprotein M affecting lipid metabolism or just catching a ride with lipoproteins in the circulation?

Apolipoprotein M (apoM) is a novel apolipoprotein found mainly in high-density lipoproteins (HDL). Its function is yet to be defined. ApoM (25 kDa) has a typical lipocalin ?-barrel fold and a hydrophobic pocket. Retinoids bind apoM but with low affinity and may not be the natural ligands. ApoM retains its signal peptide, which serves as a hydrophobic anchor to the lipoproteins. This prevents apoM from being lost in the urine. Approximately 5% of HDL carries an apoM molecule. ApoM in plasma (1 μM) correlates strongly with both low-density lipoprotein (LDL) and HDL cholesterol, suggesting a link to cholesterol metabolism. However, in casecontrol studies, apoM levels in patients with coronary heart disease (CHD) and controls were similar, suggesting apoM levels not to affect the risk for CHD in humans. Experiments in transgenic mice suggested apoM to have antiatherogenic properties; possible mechanisms include increased formation of pre-? HDL, enhanced cholesterol mobilization from foam cells, and increased antioxidant properties. Received 28 November 2008; received after revision 15 December 2008; accepted 16 December 2008     

Studying non-alcoholic fatty liver disease with zebrafish: a confluence of optics, genetics, and physiology

Obesity is a public health crisis. New methods for amelioration of its consequences are required because it is very unlikely that the social and economic factors driving it will be reversed. The pathological accumulation of neutral lipids in the liver (hepatic steatosis) is an obesity-related problem whose molecular underpinnings are unknown and whose effective treatment is lacking. Here I review how zebrafish, a powerful model organism long-used for studying vertebrate developmental programs, is being harnessed to uncover new factors that contribute to normal liver lipid handling. Attention is given to dietary models and individual mutants. I speculate on the possible roles of non-hepatocyte residents of the liver, the adipose tissue, and gut microbiome on the development of hepatic steatosis. The highlighted work and future directions may lead to fresh insights into the pathogenesis and treatment of excess liver lipid states.     

Certain biochemical effects of garlic oil on rats maintained on high fat-high cholesterol diet

The feeding of a high fat-high cholesterol (HF-HC) diet to normal rats for 1 month increased the lipid components cholesterol and triglyceride in serum, liver and kidneys and decreased the serum albumin very significantly. Administration of garlic oil (100 mg/kg b. wt/day) for 1 month together with the HF-HC diet to another group almost nullified the lipid-increasing and albumin-decreasing effects of that diet. The reduction in total lipids, cholesterol and triglycerides and the restoration to normal level of serum albumin were highly significant in the garlic oil group. Adipose tissue triglyceride lipase activity was significantly increased in both the above groups with a much greater rise in the oil group.     

Certain biochemical effects of garlic oil on rats maintained on high fat-high cholesterol diet

Summary The feeding of a high fat-high cholesterol (HF-HC) diet to normal rats for 1 month increased the lipid components cholesterol and triglyceride in serum, liver and kidneys and decreased the serum albumin very significantly. Administration of garlic oil (100 mg/kg b. wt/day) for 1 month together with the HF-HC diet to another group almost nullified the lipid-increasing and albumin-decreasing effects of that diet. The reduction in total lipids, cholesterol and triglycerides and the restoration to normal level of serum albumin were highly significant in the garlic oil group. Adipose tissue triglyceride lipase activity was significantly increased in both the above groups with a much greater rise in the oil group.     

Lipid complexes with cationic peptides and OAKs; their role in antimicrobial action and in the delivery of antimicrobial agents

Antimicrobial agents are toxic to bacteria by a variety of mechanisms. One mechanism that is very dependent on the lipid composition of the bacterial membrane is the clustering of anionic lipid by cationic antimicrobial agents. Certain species of oligo-acyl-lysine (OAK) antimicrobial agents are particularly effective in clustering anionic lipids in mixtures mimicking the composition of bacterial membranes. The clustering of anionic lipids by certain cationic antimicrobial agents contributes to the anti-bacterial action of these agents. Bacterial membrane lipids are a determining factor, resulting in some species of bacteria being more susceptible than others. In addition, lipids can be used to increase the effectiveness of antimicrobial agents when administered in vivo. Therefore, we review some of the structures in which lipid mixtures can assemble, to more effectively be utilized as antimicrobial delivery systems. We describe in more detail the complexes formed between mixtures of lipids mimicking bacterial membranes and an OAK and their usefulness in synergizing with antibiotics to overcome bacterial multidrug resistance.     

3-Hydroxy-3-methylglutaric acid and triton-induced hyperlipidemia in rats.

3-Hydroxy-3-methylglutaric acid (HMG) significantly decreased cholesterol, triglyceride and phospholipid levels in whole serum, serum beta-lipoproteins and liver of Triton-induced hyperlipidemic rats. Therapeutically 50 mg HMG/kg is equivalent to 200 mg nicotinic acid/kg in lowering all these lipid parameters. HMG may exert its hypolipidemic effect through inhibition of lipoprotein synthesis.     

Structural studies of discoidal lipoprotein A-I

Apolipoprotein A-I (apoA-I) is a major exchangeable apolipoprotein of high-density lipoproteins (HDLs), and plays an important role in reverse cholesterol transport. This process involves transport of cholesterol from peripheral tissues to the liver for processing, thereby eliminating excess cholesterol from the body. The function of apoA-I and its interaction with other components of HDL, including lecithin-cholesterol acyltransferase, seems to be closely linked to its structural plasticity. ApoA-I is likely to undergo changes in its structure and orientation between the various HDL subclasses and, therefore, knowledge of the precise structure of apoA-I is essential for understanding its role in the antiatherogenic properties of HDL. This review focuses on the role of apoA-I in reverse cholesterol transport and the work done by various groups to determine the structure of apoA-I in discoidal HDL particles.     

Cell density-induced changes in lipid composition and intracellular trafficking

Cell density is one of the extrinsic factors to which cells adapt their physiology when grown in culture. However, little is known about the molecular changes which occur during cell growth and how cellular responses are then modulated. In many cases, inhibitors, drugs or growth factors used for in vitro studies change the rate of cell proliferation, resulting in different cell densities in control and treated samples. Therefore, for a comprehensive data analysis, it is essential to understand the implications of cell density on the molecular level. In this study, we have investigated how lipid composition changes during cell growth, and the consequences it has for transport of Shiga toxin. By quantifying 308 individual lipid species from 17 different lipid classes, we have found that the levels and species distribution of several lipids change during cell growth, with the major changes observed for diacylglycerols, phosphatidic acids, cholesterol esters, and lysophosphatidylethanolamines. In addition, there is a reduced binding and retrograde transport of Shiga toxin in high density cells which lead to reduced intoxication by the toxin. In conclusion, our data provide novel information on how lipid composition changes during cell growth in culture, and how these changes can modulate intracellular trafficking.