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Cholesterol and Cardiovascular Disease

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Cholesterol (CHL)

  • sterol, only from animal sources

    • diet and body synthesis (liver and intestine)​

    • 1/3 from diet, 2/3 from synthesis

  • benefits:

    • cells membrane stability​

    • bile acid precursors

    • vitamin D synthesis

    • precursors for other hormones

  • issues:

    • can cause plaque build up and clots in arteries​

study question: 

  • relative to this information, what are the pros and cons of being a vegetarian?

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Cholesterol Synthesis

  • normal, healthy adults synthesize approx. 1g/day and consume 0.3g/day

  • precursor to CHL --> cytosolic acetyl CoA

    • carried from mitochondria to cytosol as citrate​

    • citrate is then converted to acetyl CoA and OAA

  • Three phases

    1. acetyl CoA units condense and form mevalonate​

    2. mevalonate forms squalene

    3. squalene cyclizes to form lanosterol, eventually forming CHL

  • regulation-feedback regulation in most tissues

    • CHL and bile salts repress synthesis of HMG CoA reductase​

  • liver HMG CoA reductase​ is also regulated by

    • phosphorylation and dephosphorylation​

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study questions: 

  • how can we up and down regulate HMG CoA reductase?

  • in what organ is the rate of cholesterol synthesis increased?

Dietary Cholesterol

Animal Foods

  • egg (especially in yolk)

  • meat

  • milk

  • tends to follow sat fats

​

Mostly occurs as CHL esters (CE)

  • must be hydrolyzed before absorption

  • micelle (requires bile acids from CHL in liver)

  • mixes all fat

  • uptake into mucosal cell

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study question: 

  • why is this?

  • digested and absorbed in the enterocyte - packaged with other lipids into chylomicrons as CEs

    • TAGs hydrolyzed by LPL at adipose tissue - storage/energy​

    • CHL returns to liver by chylomicron remnant receptor

  • 50% of dietary CHL is digested and absorbed

    • varies with diet​

      • increased with sat fat​

      • decreases with PUFA and MUFA

  • transported though lymph to liver

    • liver adds newly synthesized CHL to remnants of chylomicrons and VLDL​

Cholesterol Metabolism

  • Transport to cells - as TAGs are lost, VLDL becomes enriched with CHL as CEs

    • eventually becomes LDL​

  • cellular absorption - LDL binds to LDL receptor​

  • CHL is dumped inside via endocytosis

    • free CHL available to inhibit cell synthesis​

    • excess free CHL migrates to membrane

​

  • Reverse transport back to liver - excess picked up by HDL

    • re-esterfied via LCAT​

      • CHL + lectin = CE​

    • also by ACAT

      • CHL + FA = CE​

  • Balance between diet and endogenous synthesis to meet membrane needs

  • increased CHL in blood involves HDL and LDL

  • serum CHL can be from LDL, HDL, or VLDL

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Measuring Cholesterol

  1. measure total CHL

  2. do a TAG assay as indirect measure of VLDL 

    • due to fasting, there are no chylomicrons so all TAG will be associated with VLDL​​

  3. treat plasma so only HDL-C left

  4. get LDL-C by subtracting others from total

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  • LDL-C = TC - HDL-C - TAG/5​

    • TAG/5 assumes 20% of all TAG in VLDL​

      • friedwald equation​

  • get errors if not fasting

  • cannot use friedwald equation with hypertriglyceridemia

    • there are alternatives equations

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Syndrome X - Metabolic Syndrome

  • reduced ability for a given level of insulin to promote cellular uptake of glucose and suppress blood levels of FFAs

  • symptoms

    • hyperinsulinemia/glucose intolerance​

    • dyslipidemia

    • hypertension

    • disturbed coagulation

    • central body fat

    • elevated [uric acid]

  • Contributing Factors

    • genetic predisposition​

    • race/ethnicity

    • body weight/fat distribution

    • PA patterns

    • dietary patterns

    • smoking

  • AKA

    • Insulin Resistance Syndrome​

    • Metabolic Cardiovascular Syndrome

    • Plurimetabolic Syndrome

    • Deadly Quartet

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study question: 

  • How could CHL contribute to syndrome X?

Metabolic Syndrome and CHD Risk

  • metabolic syndrome is characterized by several mild distributions that are often overlooked

  • in combination, these abnormalities accelerate atherosclerosis and increase risk for clinical CHD

  • because these metabolic disturbances are interrelated, traditional statistical methods have underestimated the impact of joint risk factor disturbances

Cardiovascular Disease

Atherosclerosis

  • degeneratuve disease of the vascular endothelium​

  • disease process though to start in the endothelial layer

  • principle players include:

    • immune system cells​

    • lipids

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  • early response: increased adherence of monocytes and T-lymphocytes

    • LDL lipids taken up by phagocytic cells

      • phagocytic cells no engorged with lipid

      • now called foam cells​

  • uptake of foam cells causes the infiltration of more lipids into the endothelium

    • lesion known as fatty streak​

  • as lipid accumulates, the vessel becomes increasingly occluded

  • getting too narrow can obstruct blood flow, may lead to heart attack and stroke

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  • Role of inflammation

    • early response: increased adherence of monocytes and T-lymphocytes to the area​

      • produce cytokines​

      • cytokines attract phagocytes to the area

    • endothelial cells produce CAMs via a signal transduction pathway turned on by inflammatory factors and free radicals (ROS)

      • acts like glue​

      • attracts more cells to the site

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Reducing CHD Risk

  • Reduce circulating lipids

    • many treatments directed at lowering serum CHL, because it is the main component in plaque​

    • it's how CHL is distributed between LDL and HDL

  • Other treatment focal points

    • protecting endothelial function​

      • anti-inflammatory agents​

      • antioxidants

  • Improving blood flow

    • increase NO production​

    • preventing platelet aggregation

    • protect vascular integrity

  • Increasing protective compounds

    • hormone replacement therapy​

  • Reducing other risk factors

    • homocystine​

    • hyperinsulinemia

    • BP

  • The best for both prevention and treatment are lifestyle changes

Dietary Lipids

  • Some can lower CHL

    • PUFA (hypocholesterolemic) and MUFA​ (neutral)

    • omega-3 and omega-6

  • Some increase CHD risk

    • total fat, SFA (hypercholesterolemic), trans, cholesterol​

      • raises LDL-C and lowers HDL-C​

  • The specific FA is important

    • ​hypocholesterolemic, hypercholesterolemic, and neutral

      • ​hypercholesterolemic FAs may operate by:

        • suppressing secretion of bile acids​

        • enhancing CHL and LDL synthesis

          • by reducing HMG CoA reductase​

        • by inhibiting LCAT activity of receptor-mediated uptake of LDL

study question: 

  • What is the difference between â€‹hypocholesterolemic, hypercholesterolemic, and neutral FAs?

Therapeutic Lifestyle Changes Diet

Individuals are recommended to consume the following

  • less than 7% total kcal from sat fat

  • 25-35% total kcal from fat

  • less than 200mg CHL per day

  • limit sodium to 2400mg per day

  • consume enough calories to achieve or maintain a healthy weight and reduce blood CHL levels

Drug Therapy

HMG CoA reductase inhibitors (statins)

  • interrupting the formation of CHL by inhibiting HMG CoA reductase​

  • lowers LDL CHL levels

  • anti-inflammatory responses

  • plaque stability

  • endothelial functions

  • osteoporosis​

Bile sequestering agents

  • work in the intestines by promoting increased disposal of CHL and bile acids

  • bind bile salts in the intestine and allow fat, cholesterol, and bile acids to be eliminated in the stool

  • decrease CHL absorption

  • interrupted enterohepatic circulation of bile acids --> increased fecal loss of bile acids --> icnreased bile acid synthesis in liver using CHL

Fibrates

  • raises HDL CHL levels and lowers TAG levels

  • agonists of PPARα receptor

Nicotinic acid (niacin, B3)

  • —Works in the liver—affects production of lipids (lowers triglycerides, lowers LDL-C and raises HDL-C

  • —Need a dose hundreds times of RDA

©2023 by Syracuse University Dr.Margaret Voss

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