LIPID METABOLISM IN CARDIOVASCULAR

FK-UKI

Prof. Dr. drh. Maria Bintang, MS

GURU BESAR BIOKIMIA

REFERRENCE
Conova S. 2002. Unsaturate fatty acids work through ceramide to lower cholesterol production. News From Columbia Health Sciences. Vol. 1 issue 6. Medina RA, Aranda E, Verdugo C, Kato S, Owen GI. 2003. The action of ovarian hormones in cardiovascular disease. Biol Res 36: 325-341. Tyler F.D et all. 2009. Lipoproteins, cholesterol homeostasis and cardiac health. Int. J. Biol. Sci., 5 (5) 474-488

Cholesterol
Lipid that is either absorbed from dietary sources or synthesised in the liver. Essential component of cell membranes allowing them to maintain permeability & fluidity Required for the production of steroid hormones & fat soluble vitamins Some forms of cholesterol can cause atherosclerosis (LDL) and therefore metabolising cholesterol in an efficient manner is essential for health. The liver does this by monitoring cholesterol levels & altering the amount of production, absorption & bile secretion of cholesterol to maintain adequate levels.

Sources of Cholesterol
Diet De novo synthesis Cholesterol synthesized in extrahepatic tissues

Liver cholesterol pool

Secretion of HDL, LDL, and VLDL

Free cholesterol In bile

Conversion to bile salts/acids

1.

Oxidation of fatty acid to form acyl CoA

The fatty acids (as acyl CoA) are now in the mitochondrial matrix ready to be oxidised. Two carbons are cleaved from the carboxyl end of acyl CoA. The bond that is broken is between the alpha and beta carbons (hence beta oxidation) The products of beta oxidation are:
Acetyl CoA (enters citric acid cycle for complete oxidation). NADH and FADH2 (used for ATP production via electron transport chain). Acyl CoA shortened by 2 carbons (ready to go through the beta oxidation reaction sequence again)

2.

3.

4.

Cholesterol Biosynthesis in liver

Catabolism Cholesterol = Bile Acid Biosynthesis

Bile Acids Synthesis and Utilization

The end products of cholesterol utilization are the bile acids, synthesized in the liver. Synthesis of bile acids is one of the predominant mechanisms for the excretion of excess cholesterol. However, the excretion of cholesterol in the form of bile acids is insufficient to compensate for an excess dietary intake of cholesterol.

Bile acids perform four physiologically significant functions: 1. Their synthesis and subsequent excretion in the feces represent the only significant mechanism for the elimination of excess cholesterol. 2. Bile acids and phospholipids solubilize cholesterol in the bile, thereby preventing the precipitation of cholesterol in the gallbladder. 3. Facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents that render fats accessible to pancreatic lipases. 4. Facilitate the intestinal absorption of fat-soluble vitamins.

Gallstone
Gallstones develop when bile contains too much cholesterol and not enough bile salts Besides a high concentration of cholesterol, two other factors seem to be important in causing gallstones: The presence of proteins in the liver and bile that either promote or inhibit cholesterol crystallization into gallstones A lack of melatonin inhibits cholesterol secretion from thegallbladder, enhances the conversion of cholesterol to bile, and is an antioxidant, capable of reducing oxidative stress to the gallbladder

Complete gallstone cause steatorhea

1. Gastric lipase hydrolisis emulsified lipids, phospholipids, cholesterol, fatty acids and liporoteins

8 2.

3. 6.

4.

5.

Lipid Transport
A model for plasma triasyglycerol and cholesterol transport in humans

Fatty acid mobilization

The main factors that may induce a high plasma cholesterol concentration
The composition of the diet: rich in cholesterol, or in fat or excess carbohydrates, which may form first acetyl-coa and then cholesterol, Inactivity: sedentary lifestyles, such as typical of prison or university inmates, Genetic factors, in particular a defect of the LDL receptor.

Transport of exogenous cholesterol

Apolipoprotein B100 (apo B100) is a protein that plays a role in moving cholesterol around your body

pancreatic lipase (PL) lipoprotein lipase (LPL) Niemann-Pick C1-Like 1 (NPC1L1) triglyceride transfer protein (MTP) low density lipoprotein receptor (LDLR) lipoprotein related protein (LRP) Carboxyl ester lipase (CEL)

Exogenous lipid metabolism in the intestine

Cholesterol absorbed from the diet is a major contributor to levels of cholesterol in circulation. the complete abolition of dietary cholesterol absorption would reduce plasma cholesterol by up to 62% 50% of dietary cholesterol is absorbed through intestinal enterocytes, while the rest is excreted through feces

.. Exogenous lipid metabolism in the intestine

Early lipid digestion from the oral cavity to the duodenum sub-layer of the intestine, produce crude emulsions (free cholesterol, triglycerides, free fatty acids, and phospholipids) As these emulsions are delivered into the intestine, mixed with bile salt micelles, then synthesized and secreted into the intestine from the liver Total concentration of bile salt micelles is positively correlated with cholesterol absorption Catalysis of lipid emulsification into smaller droplets, which interact more readily with lipase enzymes Bile salt emulsified triglycerides and cholesteryl esters are hydrolyzed by pancreatic lipase and carboxyl ester lipase

Movement of exogenous cholesterol from the intestines to the liver

Inside enterocytes, dietary cholesterol is packaged into chylomicrons, and put into circulation initiated by the esterification of large amounts of free cholesterol by the cholesteryl transferase protein and the synthesis of triglycerides from free fatty acids by mono- and di-acylglycerol acyltransferases In the endoplasmic reticulum, cholesteryl esters, phospholipids and triglycerides are amalgamated together with ApoB-48 by the microsomal triglyceride transfer protein (MTP) While the digestion and packaging of dietary lipids into chylomicrons takes about one hour, the half life of lipids in chylomicrons is only 4.5 minutes

. Movement of exogenous cholesterol from the intestines to the liver

LPL catalyzes the hydrolysis of triglycerides in chylomicrons,a crucial process that distributes fatty acids to tissues, generates non-esterified fatty acids in plasma, and remodels chylomicrons into CRs The absence of LPL causes familial LPL deficiency, which is characterized by hypertriglyceridemia, decreased HDL and LDL, and massive accumulation of chylomicrons in plasma LDLR is responsible for uptake of cholesterol carrying lipoproteins LDLR can catalyze endocytosis of lipoproteins containing multiple copies of ApoE such as VLDL, IDL, and HDL

Cardiovascular disease (CAD)

The level of plasma cholesterol (and in particular LDLassociated cholesterol) is one of the main risk factors of atherosclerosis, the degenerative disease underlying myocardial infarction and stroke Cardiovascular disease (CAD) is a general description incorporating several pathologies including coronary heart disease, stroke and venous thrombosis Differences in the incidence of hypertensive heart disease and coronary heart disease, atherosclerosis and cardiac remodeling after myocardial infarction (MI) between males and females are well established Atherosclerosis is a progressive disease which is characterized by the accumulation of lipids and fibrous elements in the walls of large arteries and constitutes the most important factor in the growing incidence of CAD

Several risk factors of CAD

Cigarette smoking Diabetes Hypertension Elevated serum lipid concentration, have been shown to increase the incidence and accelerate the progression of the disease

Clinical symptoms of atherosclerosis

1. Lipid accumulation and connective tissue matrix production can increase plaque volume so that it encroaches on the lumen and impedes blood flow. 2. A plaque can enter an unstable phase and fissure which leads to thrombus formation. The thrombus can encroach or occlude the lumen or, alternatively, embolize, impact and occlude a smaller distal vessel. 3. Although atherosclerosis is a focal disease, it is associated with a generalized abnormality in vascular tone in affected vessels which favors vasoconstriction, especially during stress and exercise. 4. Medial atrophy and destruction can lead to aneurysm formation

Lipid accumulation
lipid accumulation in the arterial wall, caused by hyperlipidemia, is the initial step. Signs of inflammation are observed simultaneously with lipid accumulation Blood leukocytes, mediators of the immune response and inflammation, attach to the endothelial cells that line the intima The normal endothelium does not support the binding of white blood cells After atherogenic diet, endothelial cells begin to express on their surface adhesion molecules capable of binding leukocytes

Atherosclerotic lesions development

Small mechanical lesions in the vascular endothelium (the innermost layer of blood vessel walls) allow leakage of blood plasma into the muscular layers beneath. Formation of these small leakages is thought to be promoted by high blood pressure. The lipoproteins that leaked into the tissue are degraded. Because of its low solubility, cholesterol released from degraded lipoproteins precipitates. The cholesterol particles trigger invasion of phagocytic cells and in this way contribute to triggering inflammation, which in turn increases the tissue damage and turns the small, potentially reparable defects of the vessel wall into large lesions.

expression of inflammatory and adhesion molecules; initial lipid infiltration and accumulation

HRT VSMC ICAM CRP

Hormone Replacement Therapy Vascular smooth muscle cells inter-cellular adhesion molecule C Reactive Protein

Step 1 &2 : Among these adhesion molecules, VCAM- 1 and ICAM-1 bind monocytes and T lymphocytes found in early atheroma Step 3 : Increased shear stress may also induce formation by VSMC of proteoglycans that bind lipoprotein particles, facilitating their oxidative modification and further inducing an inflammatory response Step 4 & 5 : Once the leukocytes have adhered to the endothelium and an inflammatory response is initiated, monocytes penetrate the intima in response to monocyte chemoattractant protein-1 (MCP-1). Once in the arterial wall, the monocytes differentiate into macrophages in response to macrophage colonystimulating factor (M-CSF)

Plaque growth and increased LDL deposition

HRT = Hormone Replacement Therapy CRP = C Reactive Protein TNF = tumor necrosis factor beta INF = interferon gamma

Step 6 : Monocyte adhesion andmigration produce a localized inflammatory response in which tumor necrosis factor beta (TNF) and interferon gamma (INFg) are released by macrophages Step 7 & 8 : These macrophages also have increased expression of the scavenger receptor A and CD36 which internalize modified lipoproteins (minimally modified and oxLDL), accumulating cholesteryl esters in the form of cytoplasmic droplets, leading to foam cell formation which characterize the fatty streak, a hallmark of the early atherosclerotic lesion

Plaque rupture and thrombus formation

HRT = hormone replacement therapy CRP = C Reactive Protein

Steps 9-11 : As the lesion grows, it narrows the arterial lumen, interfering with blood-flow and causing clinical symptoms, such as angina pectoris or acute myocardial infarction (MI)

THE FUTURE OF EXOGENOUS HORMONES

Estrogen improves well-defined risk factors, such as lipid profiles; it also has direct effects on the myocardium, endothelium, and vascular smooth muscle (VSM). Estrogens enhance flow of cholesterol from the diet through chylomicrons and chylomicron remnants to the liver, through very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) to cells, and through reverse cholesterol transport from cells via high-density lipoprotein (HDL) to the liver to be finally eliminated in the bile and intestine Estrogen increases levels of VLDL and subsequently the levels of triglycerides, decreases LDL levels due to the up-regulation of LDL receptors, and increases HDL due to increased secretion of apoA-I and reduced removal of HDL due to a reduction in hepatic lipase activity

The future of exogenous hormones

Estrogen is widely regarded as having beneficial effects on the three layers of the arterial wall; the intima (endothelium), the media, and the adventitia. These beneficial effects include reduction in plasma fibrinogen, plasminogen activator inhibitor (PAI-1) activity, reduced LDL oxidation in plasma, enhanced glucose metabolism, and enhanced insulin resistance

The future of exogenous hormones

In the arterial endothelium, estrogen increases nitric oxide (NO) synthase activity and NO production NO is beneficial to arterial vasomotion in women who have angina pectoris due to vasospasm In the intima and media of the arterial wall, estrogen reduces calcification and secretion of inflammatory cytokines such as :
fibroblast growth factor (FGF) inter-cellular adhesion molecule (ICAM-1) vascular cell adhesion molecule (VCAM-1), endothelial- and platelet-selectin (E- and P-selectin) nuclear factor kappa B (NFkB)

The future of exogenous hormones

Progestins have been reported to oppose the estrogen-induced increase in plasma NO metabolites which indicates that progestins inhibit NO production in endothelial cells and is further evidence of the proatherogenic effects of progestins in the presence of estrogen Progestins appear to reduce the stimulatory effect of estrogens on lipoprotein transport in the bloodstream, For example : VLDL secretion is reduced; remnant removal is impaired LDL receptors are down-regulated Increasing LDL-cholesterol levels; and HDL levels are reduced in response to increased hepatic lipase activity

Unsaturated Fatty Acids Reduce Cholesterol Synthesis

Unsaturated fatty acids inhibit a transcription factor that increases cholesterol manufacture inside a cell. When active, the molecule called sterol regulatory element binding protein (SREBP), for sterol regulatory element binding proteinbinds to the cells SRE promoter and turns on genes for cholesterol synthesis. When inactive, the cell makes little of its own cholesterol.

Serum Lipoprotein
Water soluble Contain relatively large amounts of choleaterol ester, free cholesterol, phospholipids, and triglyserides in addition to the protein Base on their density in the ultracentrifuge and analysis of its componens lipoprotein are grouped as :
Group HDL LDL IDL Diameter () 50-120 180-250 250-350 Density (g/cm3) 1.063-1.210 1.019-1063 1.006-1.019 % Protein 40-55 20-25 10-20 % Phospholipid 22% 30% % Choleterol 3-10 7-15 20-30 TG 4-8 15-25 40-45

VLDL
Chylomicrons

300-800
1000-5000

0.95-1.006
< 0.95

5-10
1-2

20%

50-65
85-90

45-50
15-20

Cholesterol Level ( mg/dL)

Blood Cholesterol Level Total Cholesterol Triglycerides Low Density Cholesterol High Density Cholesterol Desirable < 200 < 150 < 130 > 50 Borderline (high) 200-240 150-500 130-160 50-35 High Risk > 240 > 500 > 240 < 35

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