LIPIDS AND LIPOPROTEINS

What are the major functions of lipids and what diseases result from lipid imbalance?  

• Major source of energy (9 kcal/g)

• Used in energy production as fatty acids

• Hydrophobic barrier for subcellular compartmentalization

• Regulators/cofactors (fat‑soluble vitamins)

• Precursors of prostaglandins and steroid hormones

• Stored in adipose tissue as triglycerides

• Must be transported in lipoproteins

• Disorders from imbalance: Obesity, Atherosclerosis → contribute to metabolic syndrome

What types of lipids are included in dietary lipid intake?  

• Triglycerides (esterified fatty acids)

• Unesterified fatty acids (free fatty acids)

• Cholesterol

• Cholesteryl esters

• Phospholipids

Where are chylomicrons synthesized and from what components?  

• Synthesized in intestinal mucosal cells

• Made from dietary lipids and apoprotein B‑48

What is the function and composition of chylomicrons?  

Function: Transport dietary lipids to peripheral tissues.

Composition:

• 82% triacylglycerols

Key apoprotein: Apo B‑48  

MTP (MTTP) - Microsomal triglyceride transfer protein : Facilitates lipid binding to Apo B‑48  

Maturation: Acquire Apo C (I, II, III) and Apo E from HDL (storage)

Release: Exocytosed into lymph → bloodstream

Note:

• MTP deficiency → abetalipoproteinemia (no “B” type protein)

  • Autosomal recessive

  • Low/absent chylomicrons

  • Severe neuropathy, acanthocytosis, steatorrhea in infancy

What does the chylomicron composition/synthesis slide emphasize?  

• Chylomicrons are synthesized in intestinal epithelial cells.

• Composition dominated by triglycerides.

• Structural apoprotein: Apo B‑48.

What apoprotein activates LPL and what are the structural proteins of VLDL/LDL vs chylomicrons?  

• Apo CII activates lipoprotein lipase (LPL).

• Structural protein of VLDL & LDL: Apo B‑100

• Structural protein of chylomicrons: Apo B‑48

What is the fate of triglycerides in chylomicrons and where is LPL located?  

• TGs are hydrolyzed by LPL → fatty acids + glycerol

• LPL is located on luminal surface of capillaries in:

  • Muscle (especially cardiac)

  • Adipose tissue

  • Lactating mammary gland

  • Lungs

  • Kidneys

  • Liver - last, doesn’t process full chylomicrons

• FFAs bind albumin for transport

• FFAs: oxidized for ATP (muscle) or stored as TG ie esterfied (adipose)

What regulates LPL and what happens in diabetes or LPL deficiency?  

• Adipose LPL has highest Km; heart LPL lowest Km

• LPL synthesis stimulated by insulin

• Low insulin → accumulation of chylomicrons & VLDL

• Insulin inhibits hormone‑sensitive lipase

• Diabetes mellitus:

  • Low insulin → low LPL + high HSL → hypertriglyceridemia

• Familial LPL deficiency (Type I hyperlipoproteinemia):

  • Autosomal recessive

  • Severe hypertriglyceridemia (>2000 mg/dL)

What happens to glycerol released from triglycerides during LPL action?  

• Glycerol is transported to the liver.

• In the liver, glycerol is phosphorylated → glycerol‑3‑phosphate.

• Glycerol‑3‑phosphate is used for:

  • Triglyceride synthesis in the fed state

  • Gluconeogenesis in the fasting state

• Blood glycerol increases when TGs are hydrolyzed by LPL.

What is the fate of chylomicron remnants and what receptors are involved?  

• Remnants contain:

  • Cholesteryl esters

  • Phospholipids

  • Apolipoproteins

  • Small amount of TG

• Remnants bind hepatocyte receptors via Apo E:

  • LDL receptor–related protein (LRP)

• Remnants contain equal cholesterol and triglycerides.

• Endocytosed and hydrolyzed in lysosomes.

How are chylomicron remnants processed after ApoE recognition?  

• ApoE binds LRP on hepatocytes.

• Endocytosis → lysosomal degradation.

• Products released into cytosol:

  • Fatty acids/Amino acids/Glycerol/Cholesterol

• Type III hyperlipoproteinemia (dysbetalipoproteinemia):

  • Defective remnant removal

  • Autosomal recessive

  • Premature atherosclerosis

  • Xanthoma striata palmaris (palmar xanthomas)

Which lipidemia is more severe: ApoCII deficiency or ApoE deficiency?  

• ApoCII deficiency causes more severe lipidemia.

• Because ApoCII is required to activate LPL, so TGs cannot be hydrolyzed at all. —> more severe

• ApoE deficiency affects remnant clearance but does not block TG hydrolysis.

What does the chylomicron metabolism slide emphasize?  

• Synthesis in intestine → lymph → blood.

• Maturation via ApoC and ApoE from HDL.

• LPL (activated by ApoCII —> goes back to HDL) hydrolyzes TGs.

• Remnants taken up by liver via ApoE‑LRP.

 What is the composition, synthesis, and function of VLDL? 

Composition:

• 52% TG (Hepatic aka endogenous)

• 22% cholesterol

• 18% phospholipids

• 8% apoproteins

Synthesis:

• From chylomicron remnants

• From TAGs not hydrolyzed in peripheral tissues

• From dietary carbohydrates (major carbon source):

  • Glucose → acetyl‑CoA → fatty acids

  • Glucose → DHAP → glycerol

  • FA + glycerol → TAG

• High‑carb intake → carbohydrate‑induced hypertriglyceridemia

• Major apoprotein: Apo B‑100

• Acquire ApoC and ApoE from HDL

• MTTP loads TG onto ApoB100

Function: Transport hepatic lipids to peripheral tissues.

What is lipogenesis and where does it occur?  

• Lipogenesis = synthesis of TGs from glucose.

• Occurs in the liver.

• Fatty acids synthesized from glucose → converted to TGs → packaged into VLDL → secreted into blood.

What happens when VLDL production exceeds secretion?  

• VLDL transports TG from liver to tissues.

• If liver TG > VLDL secretion → fatty liver (hepatic steatosis).

What happens to VLDL after LPL hydrolysis?  

• ApoC returned to HDL.

• VLDL remnants can:

  • Be internalized by liver, or

  • Be converted to IDL → LDL

• Conversion IDL → LDL requires hepatic triglyceride lipase (HTGL).

What modifications occur as VLDL becomes IDL and LDL? 

• LPL removes TG → particle becomes smaller and denser.

• ApoCII and ApoE returned to HDL.

• TG exchanged for cholesteryl esters via CETP.

• CETP deficiency → high HDL, low LDL, low CHD incidence.

Cholesteryl ester transfer protein (CETP)

What happens to VLDL triglycerides and what are the possible fates of IDL and LDL?  

• VLDL TGs are hydrolyzed by LPL → fatty acids + glycerol.

• Fatty acids:

  • Oxidized for energy (muscle)

  • Stored as TG (adipose)

• Glycerol: used by liver and tissues with glycerol kinase.

• VLDL → IDL → LDL via HTGL.

• LDL can be:

  • Endocytosed by liver

  • Endocytosed by peripheral cells

  • Oxidized and taken up by macrophage scavenger receptors → atherosclerosis

• HTGL deficiency:

  • Low LDL

  • High TG

  • High cholesterol

  • Accumulation of VLDL + chylomicron remnants

How are fatty acids from chylomicrons and VLDL converted into stored triglycerides in adipose tissue?  

• LPL releases fatty acids from TG in chylomicrons/VLDL.

• Fatty acids enter adipocytes.

• Re‑esterified with glycerol‑3‑phosphate to form TG.

• Stored in adipose cells.

What is the composition, synthesis, and function of LDL?  

Composition:

• 47% cholesterol

• 23% phospholipids

• 21% apoprotein (only Apo B‑100)

• 9% triglycerides

Synthesis:

• Formed from VLDL catabolism: VLDL → IDL → LDL

Function:

• Transports ≈60% of total body cholesterol (fasting plasma).

• 2/3 of LDL cholesterol is esterified (linoleic acid).

• Major carrier of cholesterol to peripheral tissues.

 What enzyme esterifies cholesterol in plasma and what disease results from its deficiency?  

• LCAT (lecithin:cholesterol acyltransferase) esterifies cholesterol in plasma.

• Familial LCAT deficiency:

  • Complete absence of LCAT activity

  • Esterification defects in HDL and LDL

  • Triad:

    • Diffuse corneal opacities

    • Target cell hemolytic anemia

    • Proteinuria with renal failure

• Question posed: etiologies of target cells include liver disease, hemoglobinopathies, and LCAT deficiency.

 How is LDL cleared and how does free cholesterol regulate hepatic cholesterol metabolism?  

• LDL taken up by hepatocytes via LDL receptors.

• Lysosomal degradation →

• Free cholesterolesterified by acyl-CoA cholesterol acyl

  transferase (ACAT)

  • Amino acids

• Increased free cholesterol causes:

  • ↓ HMG‑CoA reductase activity

  • ↑ ACAT activity

  • ↓ LDL receptor production

Note:

• LDL receptor deficiency → Type II hyperlipidemia (familial hypercholesterolemia) → premature atherosclerosis.

What hormone affects LDL receptor binding and what condition results from its deficiency?  

• Thyroid hormone T3 stimulates LDL receptor binding.

• Hypothyroidism → decreased LDL receptor activity → hypercholesterolemia secondary to hypothroidism

What actions can decrease total cholesterol in the bloodstream? LY

Examples include:

• Lifestyle:

  • Diet low in saturated fat

  • Increased physical activity

  • Weight loss

  • Smoking cessation

• Pharmaceutical:

  • Statins (HMG‑CoA reductase inhibitors)

  • Bile acid sequestrants

  • Ezetimibe

  • PCSK9 inhibitors

What is Lp(a), what risks does it pose, and what are its characteristics?  

• Lp(a) resembles LDL.

• Increases risk of CVD.

• More atherogenic than LDL.

• Promotes clot formation (interferes with fibrinolysis).

• Genetically determined.

• Synthesized in liver; contains Apo B‑100.

• Some patients benefit from lipoprotein apheresis (↓ Lp(a) by 75%).

• Secondary causes: CKD, nephrotic syndrome, hypothyroidism.

What is the composition, synthesis, apoproteins, and function of HDL?  

Composition:

• 50% apoproteins

• 28% phospholipids

• 19% cholesterol

• 3% triglycerides

Synthesis:

• Assembled in liver and intestine from peripheral tissue

Major apoproteins:

• Apo A‑I

• Apo A‑II

Function:

• Reverse cholesterol transport (tissues → liver)

• Free cholesterol esterified by LCAT on HDL (Cholesterol + FA → cholesterol ester)

Question posed: Predict consequences of absence of Apo A → extremely low HDL, impaired reverse cholesterol transport, ↑ CHD risk.

How does HDL deliver cholesterol to the liver and interact with other particles?  

• HDL binds hepatocytes via SR‑B1.

• Releases cholesterol esters without endocytosis.

• SR‑B1 upregulated when cholesterol demand is high.

• HDL exchanges ApoC and ApoE with chylomicrons, VLDL, and IDL.

• SR‑B1 is multifunctional

What does the recap slide emphasize about lipoprotein metabolism?  

• It summarizes the pathways of chylomicrons, VLDL, IDL, LDL, and HDL.

• Reinforces the roles of apoproteins, LPL, HTGL, CETP, and receptor‑mediated uptake.

• Highlights the flow of dietary and hepatic lipids through the bloodstream and into tissues or liver.

What is the overall summary of lipoprotein metabolism presented on this slide?  

• Chylomicrons transport dietary TG.

• VLDL transports hepatic TG.

• IDL and LDL arise from VLDL metabolism.

• LDL delivers cholesterol to tissues.

• HDL removes cholesterol from tissues and returns it to the liver.

• Apoproteins regulate enzyme activation, receptor binding, and particle stability.

KEY WORD: MILKY APPEARANCE (after 12h fasting)

What are the major apoproteins and their key characteristics?  Review

• Apo A‑I: Activates LCAT; major HDL protein.

• Apo A‑II: HDL structural protein.

• Apo B‑48: Structural protein of chylomicrons.

• Apo B‑100: Structural protein of VLDL, IDL, LDL; binds LDL receptor.

• Apo C‑II: Activates LPL.

• Apo C‑III: Inhibits LPL.

• Apo E: Required for remnant uptake by liver (chylomicron remnants, IDL).

What are the major lipid fractions in fasting serum and how is total cholesterol calculated?  

• Cholesterol carried on VLDL, LDL, HDL.

• Total cholesterol (TC) = HDL + VLDL + LDL.

• Clinical labs measure:

  • Total cholesterol/ triglycerides/HDL cholesterol

• In fasting serum, most TG are in VLDL

• VLDL cholesterol ≈ TG/5.

What is the Friedewald formula and when is it valid?  

• LDL = TC – (HDL + TG/5)

• Valid only when:

  • Fasting sample

  • TG < 400 mg/dL

• If TG > 400 mg/dL → need ultracentrifugation or direct LDL measurement.

Why is evaluating lipid fractions more accurate than total cholesterol alone?  

• Two people with same TC can have vastly different LDL, HDL, and TG.

• Example:

  • High HDL → lower CHD risk

  • Low HDL + high LDL → much higher CHD risk

• Women often have high HDL (activity dep), making TC misleading.

• Lipid fractions must be evaluated before therapy.

How do macrophage scavenger receptors contribute to plaque formation?  

• Macrophages take up oxidized LDL via scavenger receptors.

• Uptake is unregulated → foam cell formation.

• Foam cells accumulate in arterial intima → atherosclerotic plaque.

What are the positive and negative risk factors for CHD? LY

Positive risk factors:

• Age:

  • Male ≥ 45

  • Female ≥ 55 or premature menopause without estrogen therapy

• Family history of premature CHD

• Current smoking

• Hypertension

• Diabetes mellitus

• Low HDL (< 35 mg/dL)

• High Lp(a)

Negative risk factor:

• High HDL (≥ 60 mg/dL)

What secondary conditions can alter lipid levels and why are they important?  

Important because:

1. Abnormal lipids may be the first sign of an underlying condition.

2. Treating the underlying condition may eliminate the lipid disorder.

• Diabetes and alcohol use commonly cause high TG.

• Improving glycemic control or reducing alcohol lowers TG.

• Secondary causes should be evaluated before starting lipid‑lowering therapy.

What does eTable 28–1 summarize regarding lipid abnormalities?  

• Lists secondary causes of lipid abnormalities from Current Medical Diagnosis & Treatment.

• Includes conditions, medications, and metabolic disorders that alter lipid levels.

• Emphasizes that secondary causes must be evaluated before diagnosing primary lipid disorders.

What additional risk factors help predict future CHD events?  

• High‑sensitivity C‑reactive protein (hs‑CRP)

• Electron beam computed tomography (EBCT)

• Homocysteine

• Fibrinogen

• Lipoprotein (a)

• LDL particle characteristics

Treatment decisions are based on:

• Presence of clinical cardiovascular disease or diabetes

• Patient age

• LDL cholesterol > 190 mg/dL

• Estimated 10‑year cardiovascular risk

Increased fiber = increased bile excretion —> lowers cholesterol in blood from making more bile

What is the purpose of the Framingham 10‑year CHD risk table?  LY

• Assigns point values to risk factors.

• Total score estimates 10‑year CHD risk.

• Used to guide treatment decisions and preventive strategies.

What does the 10‑year risk estimation slide provide? LY

• Converts total Framingham points into a percentage risk of developing CHD within 10 years.

• Used clinically to stratify patients into low, intermediate, or high risk.

What are the clinical presentations associated with lipid abnormalities?  

• Most patients have no symptoms.

• Detected via lab testing during CVD workup or preventive screening.

• Extremely high chylomicrons or VLDL (TG > 1000 mg/dL): eruptive xanthomas.

• High LDL: tendinous xanthomas (Achilles, patella, hand).

• Tendon xanthomas suggest genetic hyperlipidemias.

• Familial combined hyperlipidemia (FCHL):

  • Most common inherited dyslipidemia

  • Elevated LDL‑C + TG

  • Variable phenotypes

  • Strong family history of premature ASCVD

  • Tendon xanthomas absent (distinguishes from FH)

• Lipemia retinalis: TG > 2000 mg/dL → cream‑colored retinal vessels.

What condition is shown in the lipemia retinalis image and what causes it?  

• Lipemia retinalis.

• Caused by extremely high triglycerides (> 2000 mg/dL).

• Retinal vessels appear cream‑colored.

What clinical findings are shown in the eruptive xanthoma?  

• Eruptive xanthomas on the arm in untreated hyperlipidemia + diabetes mellitus.

• Xanthelasma on eyelids.

• Tuberous xanthomas.

• Elbow xanthomas.

• All associated with severe hyperlipidemia.