Lipoprotein metabolism and its relationship to atherosclerosis

lipoprotein metabolism and its relationship to atherosclerosis

Lipids are fatty substances that are required for maintenance of normal bodily function. Cholesterol and triglycerides are the major lipids that circulate in blood. Effect of fish oil on atherosclerosis and lipoprotein metabolism In addition, the monkeys fed fish oil had less atherosclerosis in the coronary arteries and in the aorta. Thus .. Relationships with plasma lipids and high density lipoproteins. Lipoprotein metabolism and its relationship to atherosclerosis M.S. Brown, J.L. GoldsteinHow LDL receptors influence cholesterol and atherosclerosis.

Individuals lacking in the gene encoding CETP have been identified as having lower cardiovascular risk and the enzyme has become a pharmaceutical target see module 4 for more on CETP inhibitors as a drug class. Nascent HDL, in the form of flattened discs, is generated from LPL- mediated lipolysis of triglyceride rich lipoproteins TRLs, including VLDL and cChylomicronsor triglyceride rich lipoproteins TRLs or secreted directly from the gut or liver, and enters plasma and where it picks up additional exchangeable apolipoproteins.

Free cholesterol is removed from deposits in peripheral tissues via ATP-binding cassette A1 ABCA1 activated by apoA1, rapidly esterified by the action of lecithin cholesterol acyl transferase LCAT and funnelled into the core of the new HDL particle converting it to the mature spherical form.

Finally the cholesterol-enriched HDL particle returns cholesterol to the liver for biliary excretion. The cholesterol-depleted HDL particles can then return to the circulation to undertake more reverse cholesterol transport. Cholesterol homeostasis The rate of cholesterol formation by the liver and absorption by the small intestine is highly responsive to the cellular level of cholesterol.

This feed back regulation is controlled primarily by changes in the amount and activity of 3-hydroxy-3 methylglutaryl CoA reductase HMGCoA reductase. This enzyme catalyses formation of mevalonate, the committed step in cholesterol biosynthesis.

For more detail on this process of cholesterol homeostasis, see dropdown box. Cholesterol homeostasis click to enlarge Cholesterol homeostasis The concentration of free cholesterol determines the fluidity and function of cell membranes and regulates overall cholesterol homeostasis see figure 6.

When hepatic cholesterol is reduced by export in lipoproteins or conversion to bile acids, membrane cholesterol concentration falls and SREBP-2 activates the enzymes of cholesterol synthesis, including HMG-Co-A reductase which is the rate limiting step in the pathway. Conversely, when hepatic cholesterol is increased by receptor mediated uptake of cholesterol in lipoproteins or return of cholesterol to the liver by HDL particles, membrane cholesterol increases, preventing activation of SREBP-2 and leading to LDL-receptor downregulation and inactivation of cholesterol synthesis.

Lipoproteins and atherogenesis The majority of circulating cholesterol is carried in LDL which is the lipoprotein most closely associated with the development of atherosclerosis.

Steps in atherogenesis The steps in atherogenesis are summarised in table 2.

lipoprotein metabolism and its relationship to atherosclerosis

Under normal circumstances, LDL may pass from the plasma into the subendothelial space and return to the liver to be removed from the circulation. At this point it has performed its transport functions without being taken up by macrophages and indeed is unable to stimulate foam cell formation in vitro.

However, if retention of the LDL in the endothelial space is increased, due to endothelial injury e.

Metabolism - Lipoprotein Metabolism - Chylomicrons, VLDL, IDL, LDL, & HDL

Oxidised or otherwise modified LDL are retained in the subendothelial space and are taken up by monocyte-derived macrophages via the scavenger receptor leading to the formation of foam cells, and the development of arterial sub-endothelial fatty streaks, the precursor of atheroma. Small dense LDL particles, typically found in found in association with prolonged postprandial hypertrigylceridaemia and low HDL cholesterol, appear more susceptible to oxidation which may make them more atherogenic.

These are considered the most highly atherogenic of all. Other atherogenic lipoproteins readily retained in the subendothelial space include glycated LDL and lipoprotein a.

Atherosclerosis & Lipoproteins | Physiology & Biophysics

HDL are, however, able to penetrate deep into the subendothelial space and are able to remove oxidised lipid from macrophages and prevent foam cell formation, in addition to having a protective effect on the endothelium.

Reduction of HDL particle numbers or functional activity is therefore pro-atherogenic. Figure 7 shows the progression of atherosclerosis. For more information on the process of atherosclerotic plaque development, please visit module 3 of our angina e-learning programme. The progression of atherosclerosis click to enlarge Apolipoproteins Apolipoproteins are proteins that bind lipids to form lipoproteins.

They transport lipids through the lymphatic and circulatory systems.

  • There was a problem providing the content you requested
  • Atherosclerosis & Lipoproteins

They also serve as enzyme cofactors, receptor ligands, and lipid transfer carriers that regulate the metabolism of lipoproteins and their uptake in tissues.

For examples of their beneficial role e.

Lipids module 1: lipid metabolism and its role in atherosclerosis

Apolipoproteins Apolipoproteins B and B48 are two proteins produced from the same gene, due to editing of mRNA in the gut. ApoB48 is exclusive to chylomicrons and chylomicron remnants. ApoE and apoC-II can transfer between particles.

lipoprotein metabolism and its relationship to atherosclerosis

Lipoprotein a is a highly atherogenic and thrombogenic lipoprotein formed by covalent bonding between the apolipoprotein B of the LDL particle and apolipoprotein aan apparently vestigial plasminogen-like protein which increases its retention in the artery wall see figure 8. Olga Gursky The long-term goal of our work is to determine in molecular detail the energetics-structure-function relationship in exchangeable apolipoproteins and lipoproteins.

Exchangeable apolipoproteins are water-soluble protein components of lipoproteins that mediate lipid and cholesterol transport and metabolism and play crucial roles in the pathogenesis of atherosclerosis, stroke and other human disorders.

Structural stability and compositional variability of apolipoproteins are essential for their functions, and have to be understood in detail in order to elucidate molecular mechanisms of lipoprotein action. Our work addresses this long-term goal through detailed studies of the thermodynamics, kinetics, structure, and lipid binding function of plasma apolipo-proteins, such as human apoC-1 57 amino acids.

Energetic and structural analyses of lipid-free and lipid-bound human apoC-1 and a series of its point mutants targeted towards specific structural regions is carried out in our laboratory by using a combination of far- and near-UV circular dichroism and fluorescence spectroscopy, electron microscopy, differential scanning calorimetry, and x-ray diffraction methods. The results will provide the energetic and structural basis for understanding molecular mechanisms of lipoprotein action in normal and diseased state.

Haya Herscovitz Our laboratory focuses on the mechanisms that regulate the assembly and secretion of very low density lipoproteins VLDLthe precursors of low density lipoproteins LDL which play an important role in the pathogenesis of heart disease and stroke.

Lipoprotein metabolism and its relationship to atherosclerosis.

The assembly of VLDL is initiated by apolipoprotein B, a very large glycoprotein with a unique capacity to recruit large amounts of triacylglycerols TAG. By utilizing biochemical, cell and molecular biological methods we have characterized the ability of N-terminal domains of apoB expressed by transfected cells that do not normally secrete lipoproteins to bind phospholipids and TAG to form lipoproteins.

Nonetheless, apoB has the capacity to bind phospholipids to form lipid-rich particles in vitro. Furthermore, it binds tightly and irreversibly to emulsions modeling TAG-rich lipoproteins. Understanding the molecular details of the assembly of apoB into VLDL will ultimately allow us to devise means to modulate the level of secreted VLDL, thereby reducing the risk of heart disease and stroke. We use a combination of biophysical, molecular biological, and computational methods to investigate and model the N-terminal region of this very large protein.

lipoprotein metabolism and its relationship to atherosclerosis

Our long term goal is to understand and develop drugs that modulate the secretion of the precursors of LDL. Graham Shipley Our research concentrates on structural studies of membrane receptors, such as the low-density lipoprotein LDL receptor.

lipoprotein metabolism and its relationship to atherosclerosis