Cholesterol, Atherosclerosis and Fatty Liver

Dr. Arvind Kumar

Introduction

  • Cholesterol is a vital sterol lipid essential for normal structure and function of cell membranes, synthesis of steroid hormones, bile acids, and vitamin D.

  • The liver plays a central role in cholesterol metabolism, regulating its synthesis, utilization, storage, and transport through lipoproteins.

  • Disturbance in lipid metabolism leads to hypercholesterolemia, which is a major biochemical risk factor for atherosclerosis and coronary heart disease.

  • Atherosclerosis is a chronic inflammatory condition characterized by cholesterol and lipid deposition in arterial walls, resulting in reduced blood flow and ischemic complications.

  • Low-density lipoprotein (LDL) is atherogenic, whereas high-density lipoprotein (HDL) is cardioprotective, making lipid profile assessment clinically important.

  • Fatty liver disease develops due to abnormal accumulation of triglycerides in hepatocytes, commonly associated with metabolic disorders, malnutrition, and alcohol intake.

  • Lipotropic factors such as choline and methionine prevent fatty liver by promoting hepatic lipid mobilization and lipoprotein synthesis.

  • Lifestyle factors including diet, physical inactivity, obesity, and smoking significantly influence cholesterol levels and cardiovascular risk.

  • Dietary and lifestyle modifications are cornerstone preventive strategies for coronary heart disease and metabolic liver disorders.

  • Understanding cholesterol metabolism, atherosclerosis, and lipotropic factors is essential for prevention, diagnosis, and management of cardiovascular and hepatic diseases.

 

Cholesterol

  • Cholesterol is a sterol (steroid alcohol) containing a cyclopentanoperhydrophenanthrene nucleus with 27 carbon atoms.

  • It is an amphipathic molecule, having:

    • A hydroxyl (–OH) group → hydrophilic

    • A hydrocarbon ring and side chain → hydrophobic

  • Cholesterol is insoluble in water and therefore transported in plasma as lipoprotein complexes.

  • Sources of cholesterol:

    • Endogenous synthesis (70–80%) – mainly in the liver, intestine, adrenal cortex, and gonads

    • Dietary cholesterol (20–30%) – obtained from animal foods (eggs, milk, meat)

  • Site of synthesis:

    • Cytosol and endoplasmic reticulum of cells

    • Liver is the principal organ regulating whole-body cholesterol homeostasis

  • Rate-limiting step of synthesis:

    • Conversion of HMG-CoA to mevalonate

    • Catalyzed by HMG-CoA reductase (key regulatory enzyme)

  • Regulation of cholesterol synthesis:

    • Feedback inhibition by intracellular cholesterol

    • Hormonal control:

      • Insulin → increases synthesis

      • Glucagon → decreases synthesis

    • Inhibited by statin drugs

  • Plasma transport of cholesterol occurs via lipoproteins:

    • LDL → transports cholesterol from liver to peripheral tissues

    • HDL → removes excess cholesterol from tissues (reverse cholesterol transport)

  • Cholesterol exists in two forms in plasma:

    • Free cholesterol

    • Esterified cholesterol (cholesteryl esters)

  • Cholesterol esters are formed by:

    • LCAT enzyme in plasma

    • ACAT enzyme inside cells

  • Excretion of cholesterol:

    • Converted into bile acids and bile salts

    • Excreted via bile and feces

    • Cholesterol itself cannot be completely degraded to CO₂ and water

  • Physiological balance of synthesis, utilization, and excretion is essential to prevent hypercholesterolemia and atherosclerosis.

 

Functions of Cholesterol

  • Structural component of cell membranes

    • Cholesterol is an essential constituent of plasma membranes.

    • Maintains membrane fluidity, stability, and permeability.

    • Prevents excessive rigidity at low temperatures and excess fluidity at high temperatures.

  • Formation of lipid rafts

    • Cholesterol participates in lipid raft formation.

    • Lipid rafts are important for cell signaling, receptor function, and membrane trafficking.

  • Precursor of steroid hormones

    • Cholesterol is the parent molecule for all steroid hormones, including:

      • Glucocorticoids (cortisol)

      • Mineralocorticoids (aldosterone)

      • Sex hormones (estrogen, progesterone, testosterone)

  • Precursor of bile acids and bile salts

    • In the liver, cholesterol is converted into bile acids.

    • Bile salts aid in emulsification, digestion, and absorption of dietary fats and fat-soluble vitamins (A, D, E, K).

  • Precursor of vitamin D

    • 7-dehydrocholesterol in skin is converted to vitamin D₃ on exposure to sunlight.

    • Vitamin D is essential for calcium and phosphorus homeostasis and bone health.

  • Role in nervous system

    • Cholesterol is a major component of myelin sheath.

    • Essential for rapid nerve impulse conduction and normal brain function.

  • Cell growth and differentiation

    • Cholesterol is required for cell division, growth, and tissue repair.

    • Plays a role in embryonic development.

  • Regulation of membrane-bound enzymes

    • Influences the activity of enzymes and receptors embedded in the cell membrane.

  • Source of biologically active molecules

    • Serves as a precursor for several biologically important molecules involved in metabolism and signaling.

  • Clinical relevance

    • Adequate cholesterol is essential for normal physiology.

    • Excess cholesterol, particularly LDL cholesterol, contributes to the development of atherosclerosis and coronary heart disease.

 

Atherosclerosis

Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries, characterized by lipid accumulation, fibrous plaque formation, and luminal narrowing, leading to ischemic heart disease and stroke.

Pathogenesis of Atherosclerosis 

  1. Endothelial injury (smoking, diabetes, hypertension)

  2. Increased permeability to LDL

  3. Oxidation of LDL in subendothelial space

  4. Macrophage uptake via scavenger receptors

  5. Formation of foam cells

  6. Development of fatty streaks

  7. Smooth muscle proliferation

  8. Fibrous plaque → arterial narrowing

Molecules Involved

  • Oxidized LDL

  • Cytokines (IL-1, TNF-α)

  • Adhesion molecules

  • Reactive oxygen species

 

Clinical Consequences

Atherosclerosis leads to progressive narrowing and hardening of arteries, resulting in reduced blood supply to vital organs.

1. Coronary Artery Disease (CAD)

  • Most common and serious consequence

  • Reduced blood flow to myocardium

  • Leads to:

    • Angina pectoris

    • Myocardial infarction (heart attack)

    • Sudden cardiac death

2. Cerebrovascular Disease

  • Atherosclerosis of carotid and cerebral arteries

  • Causes:

    • Transient ischemic attack (TIA)

    • Ischemic stroke

    • Cognitive impairment

3. Peripheral Arterial Disease (PAD)

  • Affects arteries of lower limbs

  • Clinical features:

    • Intermittent claudication

    • Rest pain

    • Non-healing ulcers

    • Gangrene

4. Renal Artery Atherosclerosis

  • Reduced renal blood flow

  • Causes:

    • Secondary hypertension

    • Chronic kidney disease

5. Aortic Atherosclerosis

  • Weakening of arterial wall

  • Leads to:

    • Aortic aneurysm

    • Aortic dissection

6. Thromboembolism

  • Rupture of atherosclerotic plaque

  • Platelet aggregation and thrombus formation

  • Acute vascular occlusion

 

Risk Factors 

A. Non-Modifiable Risk Factors

  • Age – risk increases with advancing age

  • Sex – males are at higher risk; post-menopausal females also vulnerable

  • Genetic predisposition – family history of cardiovascular disease

  • Ethnicity – higher prevalence in certain populations

B. Modifiable Risk Factors

  • Hyperlipidemia

    • Increased LDL-cholesterol

    • Decreased HDL-cholesterol

  • Hypertension

    • Causes endothelial damage

  • Diabetes mellitus

    • Increases LDL oxidation

    • Accelerates plaque formation

  • Smoking

    • Increases oxidative stress

    • Reduces HDL

  • Obesity

    • Associated with dyslipidemia and insulin resistance

  • Sedentary lifestyle

  • Unhealthy diet

    • High saturated fat and trans fat intake

  • Psychological stress

  • Alcohol abuse

 

Prevention

Prevention focuses on risk factor modification, lifestyle changes, and dietary control.

A. Lifestyle Modifications

  • Regular physical activity (30–45 minutes/day)

  • Weight reduction and maintenance of normal BMI

  • Smoking cessation

  • Stress management (yoga, meditation)

  • Adequate sleep

  • Regular health check-ups

B. Dietary Modifications

  • Reduce intake of:

    • Saturated fats

    • Trans fats

    • Cholesterol-rich foods

  • Increase intake of:

    • Fruits and vegetables (antioxidants)

    • Whole grains (dietary fiber)

    • Omega-3 fatty acids (cardioprotective)

  • Prefer:

    • Unsaturated fats over saturated fats

  • Limit refined sugars and processed foods

C. Control of Metabolic Disorders

  • Proper management of:

    • Diabetes mellitus

    • Hypertension

    • Dyslipidemia

  • Regular lipid profile monitoring

D. Pharmacological Prevention (High-Risk Individuals)

  • Statins (reduce LDL-cholesterol)

  • Antihypertensive drugs

  • Antiplatelet therapy (as advised)

  • Glycemic control medications

 

Hepatic Steatosis

  • Fatty liver is a metabolic disorder characterized by abnormal accumulation of triglycerides within hepatocytes.

  • Normally, fat content of liver is <5% of liver weight; values above this indicate fatty liver.

  • It is a reversible condition in early stages, but may progress to inflammation, fibrosis, and cirrhosis if untreated.

Types of Fatty Liver

1. Alcoholic Fatty Liver Disease (AFLD)

  • Caused by chronic alcohol consumption

  • Alcohol increases NADH/NAD⁺ ratio

  • Inhibits fatty acid oxidation

  • Leads to triglyceride accumulation

2. Non-Alcoholic Fatty Liver Disease (NAFLD)

  • Occurs in non-alcoholics

  • Associated with:

    • Obesity

    • Type 2 diabetes mellitus

    • Dyslipidemia

    • Metabolic syndrome

  • Most common form in modern population

3. Nutritional Fatty Liver

  • Due to protein malnutrition

  • Deficiency of lipotropic factors

  • Seen in:

    • Kwashiorkor

    • Prolonged starvation

4. Drug- and Toxin-Induced Fatty Liver

  • Caused by drugs like:

    • Tetracycline

    • Corticosteroids

    • Chemotherapeutic agents

  • Exposure to toxins (carbon tetrachloride)

5. Pregnancy-Related Fatty Liver

  • Rare but severe

  • Due to mitochondrial dysfunction of fatty acid oxidation

 

Biochemical Basis of Fatty Liver

Fatty liver develops due to imbalance between lipid synthesis, utilization, and export.

Major Biochemical Mechanisms

  1. Increased Fatty Acid Influx

    • Excess free fatty acids from adipose tissue

    • Common in obesity and diabetes

  2. Increased Triglyceride Synthesis

    • Excess acetyl-CoA converted to fatty acids

    • Enhanced esterification in hepatocytes

  3. Decreased β-Oxidation

    • Alcohol and toxins inhibit mitochondrial oxidation

    • Reduced fatty acid breakdown

  4. Defective Lipoprotein Synthesis

    • Reduced synthesis of apoproteins

    • Impaired VLDL formation

  5. Impaired Lipid Export

    • Triglycerides not transported out of liver

    • Accumulate within hepatocytes

  6. Deficiency of Lipotropic Factors

    • Reduced phospholipid synthesis

    • Failure of triglyceride mobilization

 

Lipotropic Factors

  • Lipotropic factors are substances that promote removal of fat from the liver by enhancing lipid transport and metabolism.

  • They prevent or correct fatty liver.

Important Lipotropic Factors

Lipotropic Factor Biochemical Role
Choline Phosphatidylcholine synthesis
Methionine Methyl group donor
Inositol Lipoprotein synthesis
Betaine Transmethylation reactions
Vitamin B12 One-carbon metabolism
Folic acid Methyl transfer reactions
Protein Apoprotein synthesis

 

Mechanism of Action of Lipotropic Factors

  • Enhance synthesis of phospholipids, especially phosphatidylcholine

  • Promote formation of VLDL particles

  • Facilitate export of triglycerides from liver to circulation

  • Improve hepatic lipid mobilization

  • Prevent intracellular fat accumulation

  • Maintain normal liver structure and function

In deficiency states → triglycerides remain trapped in liver → fatty liver develops

Clinical Significance

  • Fatty liver is one of the earliest manifestations of metabolic disorders

  • Early diagnosis prevents progression to:

    • Steatohepatitis

    • Fibrosis

    • Cirrhosis

    • Hepatocellular carcinoma

  • Lipotropic factors have:

    • Preventive role in fatty liver

    • Therapeutic importance in malnutrition

  • Lifestyle modification and dietary correction are essential

  • Biochemically important in:

    • Diabetes

    • Obesity

    • Alcoholism

    • Cardiovascular risk assessment

 

MCQs

1. Cholesterol is best described as a

A. Fatty acid
B. Phospholipid
C. Sterol
D. Triglyceride

Answer: C

2. The major site of cholesterol synthesis is

A. Kidney
B. Liver
C. Muscle
D. Brain

Answer: B

3. Rate-limiting enzyme in cholesterol synthesis is

A. Acetyl-CoA carboxylase
B. HMG-CoA reductase
C. LCAT
D. ACAT

Answer: B

4. LDL cholesterol is termed atherogenic because it

A. Removes cholesterol from tissues
B. Transports cholesterol to tissues
C. Inhibits plaque formation
D. Activates lipoprotein lipase

Answer: B

5. HDL cholesterol is protective due to its role in

A. Fat absorption
B. Reverse cholesterol transport
C. Triglyceride synthesis
D. LDL oxidation

Answer: B

6. Normal total cholesterol level is

A. <150 mg/dL
B. <180 mg/dL
C. <200 mg/dL
D. <250 mg/dL

Answer: C

7. Cholesterol is a precursor of all except

A. Steroid hormones
B. Bile acids
C. Vitamin D
D. Insulin

Answer: D

8. Atherosclerosis primarily affects

A. Veins
B. Capillaries
C. Large and medium arteries
D. Lymphatics

Answer: C

9. Initial lesion of atherosclerosis is

A. Fibrous plaque
B. Thrombus
C. Fatty streak
D. Calcification

Answer: C

10. Foam cells are derived from

A. Neutrophils
B. Macrophages
C. Lymphocytes
D. Platelets

Answer: B

11. Oxidized LDL contributes to atherosclerosis by

A. Reducing inflammation
B. Activating macrophage scavenger receptors
C. Increasing HDL synthesis
D. Inhibiting platelet aggregation

Answer: B

12. Major lipid present in atherosclerotic plaque is

A. Phospholipid
B. Triglyceride
C. Cholesteryl ester
D. Free fatty acid

Answer: C

13. Most common clinical consequence of atherosclerosis is

A. Renal failure
B. Coronary heart disease
C. Liver cirrhosis
D. Anemia

Answer: B

14. Angina pectoris results from

A. Complete coronary occlusion
B. Reduced myocardial blood supply
C. Valve stenosis
D. Arrhythmia

Answer: B

15. A non-modifiable risk factor for atherosclerosis is

A. Smoking
B. Obesity
C. Age
D. Diet

Answer: C

16. Smoking increases atherosclerosis by

A. Increasing HDL
B. Reducing oxidative stress
C. Causing endothelial damage
D. Lowering LDL

Answer: C

17. Diabetes mellitus accelerates atherosclerosis due to

A. Hypoglycemia
B. Increased LDL oxidation
C. Increased HDL
D. Reduced inflammation

Answer: B

18. Best lifestyle measure to increase HDL is

A. High sugar intake
B. Regular physical exercise
C. Smoking
D. Trans fats

Answer: B

19. Omega-3 fatty acids are beneficial because they

A. Increase LDL
B. Reduce inflammation and triglycerides
C. Promote plaque formation
D. Increase cholesterol synthesis

Answer: B

20. Coronary heart disease prevention primarily involves

A. Surgery
B. Lifestyle modification
C. Antibiotics
D. Steroids

Answer: B

21. Fatty liver is characterized by accumulation of

A. Cholesterol
B. Phospholipids
C. Triglycerides
D. Free glucose

Answer: C

22. Normal fat content of liver is

A. <2%
B. <5%
C. <10%
D. <15%

Answer: B

23. Most common type of fatty liver worldwide is

A. Alcoholic fatty liver
B. Drug-induced fatty liver
C. Non-alcoholic fatty liver disease
D. Pregnancy-related fatty liver

Answer: C

24. Alcohol causes fatty liver mainly by

A. Increasing β-oxidation
B. Decreasing NADH
C. Increasing NADH/NAD⁺ ratio
D. Increasing lipoprotein export

Answer: C

25. NAFLD is commonly associated with

A. Tuberculosis
B. Metabolic syndrome
C. Anemia
D. Vitamin A deficiency

Answer: B

26. Fatty liver is reversible in

A. All stages
B. Early stages
C. Cirrhosis
D. Hepatocellular carcinoma

Answer: B

27. Increased free fatty acid influx to liver occurs in

A. Starvation
B. Obesity
C. Hypothyroidism
D. All of the above

Answer: D

28. Defective VLDL formation leads to

A. Hypolipidemia
B. Fatty liver
C. Increased HDL
D. Ketosis

Answer: B

29. Lipotropic factors primarily prevent fatty liver by

A. Increasing fat intake
B. Inhibiting triglyceride synthesis
C. Enhancing lipid export from liver
D. Decreasing bile secretion

Answer: C

30. Most important lipotropic factor is

A. Vitamin C
B. Choline
C. Vitamin A
D. Calcium

Answer: B

31. Choline deficiency leads to fatty liver due to impaired

A. β-oxidation
B. Phospholipid synthesis
C. Glycogen synthesis
D. Cholesterol excretion

Answer: B

32. Methionine acts as a lipotropic factor by

A. Acting as antioxidant
B. Providing methyl groups
C. Reducing cholesterol absorption
D. Inhibiting LDL

Answer: B

33. Vitamin B12 is important in fatty liver prevention due to

A. Energy production
B. One-carbon metabolism
C. Calcium absorption
D. Antioxidant activity

Answer: B

34. Inositol helps prevent fatty liver by

A. Enhancing bile secretion
B. Promoting lipoprotein synthesis
C. Increasing insulin secretion
D. Decreasing fatty acid uptake

Answer: B

35. Protein deficiency causes fatty liver due to

A. Increased oxidation
B. Decreased apoprotein synthesis
C. Increased bile acid formation
D. Increased HDL

Answer: B

36. Fatty liver seen in malnutrition is due to deficiency of

A. Carbohydrates
B. Lipotropic factors
C. Fat-soluble vitamins
D. Electrolytes

Answer: B

37. Lipotropic factors mainly help in formation of

A. LDL
B. HDL
C. VLDL
D. Chylomicrons

Answer: C

38. Failure of triglyceride export results in

A. Hypolipidemia
B. Hepatic steatosis
C. Atherosclerosis
D. Ketosis

Answer: B

39. Early fatty liver is usually

A. Irreversible
B. Asymptomatic
C. Painful
D. Fatal

Answer: B

40. Long-standing fatty liver may progress to

A. Hepatitis
B. Fibrosis
C. Cirrhosis
D. All of the above

Answer: D

41. Best dietary approach to prevent fatty liver is

A. High fat diet
B. Balanced diet with adequate protein
C. High sugar intake
D. Fasting

Answer: B

42. HDL protects against atherosclerosis by

A. Increasing LDL uptake
B. Removing cholesterol from plaques
C. Increasing triglycerides
D. Causing vasoconstriction

Answer: B

43. Statins reduce cholesterol by inhibiting

A. ACAT
B. LCAT
C. HMG-CoA reductase
D. Lipoprotein lipase

Answer: C

44. Atherosclerosis is now considered a

A. Pure lipid disorder
B. Infectious disease
C. Chronic inflammatory disease
D. Genetic disorder only

Answer: C

45. Major dietary risk factor for CHD is

A. Fiber
B. Omega-3 fatty acids
C. Saturated and trans fats
D. Antioxidants

Answer: C

46. Peripheral arterial disease commonly presents as

A. Chest pain
B. Shortness of breath
C. Intermittent claudication
D. Jaundice

Answer: C

47. Lipotropic factors are especially important in

A. Kidney diseases
B. Liver disorders
C. Lung diseases
D. Brain tumors

Answer: B

48. Reverse cholesterol transport is mediated mainly by

A. LDL
B. VLDL
C. HDL
D. Chylomicrons

Answer: C

49. Most effective preventive strategy for CHD is

A. Drugs alone
B. Surgery
C. Early lifestyle modification
D. Antibiotics

Answer: C

50. Key biochemical event in atherosclerosis initiation is

A. Cholesterol synthesis
B. LDL oxidation
C. HDL formation
D. Triglyceride hydrolysis

Answer: B