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Bile Acids
Steroid Hormones
Protein modification

Fatty Acids

Fuel, prostanoids


FA for Fuel, Prostanoids
Protein modification


Disperse Lipids (insoluble) in blood
- foriming micelles in hydophillicblood,

proteins attached to lipoprotein shell that regulate enzymes, transfer lipids, bind to cell receptors

Structure of a Typical Lipoprotein

Different Classes of Lipoproteins

Chylomicrons and VLDL

known collectively as triglyceride-rich lipoproteins) transport dietary and endogenous triglyceride respectively.

After their triglyceride has been depleted, they are known as chylomicron remnants and intermittent density lipoproteins (IDL) respectively. IDL are precursors for low-density lipoproteins (LDL) which transport cholesterol to the periphery


Lipoprotein (a) which is distinguished by the presence of a unique apolipoprotein that resists LDL receptor uptake


The smallest particles consist of cholesterol and phospholipid rich high-density lipoproteins (HDL) which are responsible for reverse cholesterol transport

apolipoprotein B100

The apolipoprotein B100 containing lipoproteins (VLDL, IDL, LDL and lipoprotein (a) represent the lipoproteins which are most likely to contribute to atherosclerotic cardiovascular disease.

AB100 artery damage

Intestinal Absorption of Dietary Lipids and Biliary Cholesterol:
Drugs Acting Here

- bile acid squestrants
-Plant stanols and sterols
- Ezetimibe

bile acid squestrants

inhibit bile acid reabsorption in the ileum, causing hepatic bile acid deficiency. This deficiency promotes compensatory increase in bile acid synthesis from hepatic cholesterol, which is replenished through increased hepatic uptake of LDL/chylomicron from plasma and increased hepatic cholesterol synthesis

Plant stanols and sterols

are thought to displace cholesterol from micelles, preventing its uptake at the brush border membrane and reducing the amount of cholesterol transported to the liver. Reduced delivery of dietary/biliary cholesterol to the liver effectively increases clearance of LDL (and LDL-C) particles from plasma.


selectively inhibits the uptake of micellar cholesterol into intestinal epithelial cells and substantially reduces the amount of cholesterol from diet and bile that is transported to the liver, thereby resulting in compensatory increase in LDL clearance by the liver and reduction in plasma LDL-C levels. The mechanism of action of ezetimibe is thought to involve selective inhibition of the putative sterol transporter on the brush border surface of intestinal epithelial cells.

Intestinal Absorption of Dietary Lipids and Biliary Cholesterol

1. Cholestrol from the diet (1/3 or 400mg/day) and Bile (2/3 1200mg/day) enter small intestine
2. Cholestrol gets emulsified by bile salts into micelles
3. Micelles deliver cholestrol to brush border
4. Cholestrol goes from brush border into duodenal and jejunal enterocytes (sterol transporter NPC1L1)
5. After abs. it can be exported back from the enterocyte into the intestinal lumen by the ABC transporter ABCG5/G8
6. Cholestrol that remains is esterified and packaged into chylomicrons and released into the lymohatics
7. Bile salts are mostly reabs. by the IBAT (intestinal bile acid transporter) and transported back to the liver (hepatic portal)


diet enriched in n-3 fatty acids decreases the gene expression of NPC1L1 in duodenum and jejunum

Exogenous TG metabolism

1. Dietary fat broken down into constituent fatty acids
2. TG combined with Apoprotein B and secreted into the the thoracic duct as chylomicrons
3. Activate by a Apoprotein C to mediate TG hydrolysis fatty acids released and feuse to nearby tissue


Orlistat (intestinal lipase inhibitor) blocks dietary fat digestion

Endogenous TG metabolism

1. Hepatic TGs production results in the formation of VLDL

Cholestrol Delivery via LDL

The expression of LDLRs is also affected by low hepatocyte cholesterol levels, which activate a set of transcription factors called sterol regulatory element-binding proteins (SREBPs). While SREBPs increase the uptake of LDL by increasing the overall expression of LDLRs, they also increase PCSK9 expression, resulting in increased degradation of LDLRs and limited clearance of LDL-cholesterol from the blood.


Cholestrol Abundance

Cholesterol delivery via LDL-R alters intracellular membrane cholesterol and SREBP, which
# Reduces cholesterol synthesis via HMGCoAR
# Reduces LDL-R synthesis
# Increases storage as Ester

HDL and reverse Cholesterol Transport

- excess free cholestrol, accumulate in cell membrane regions aka "lipid rafts"
- these iteractwith apoAI in ECF
- the free cholestrol goes then to the apoAI and amkes Nascent dicoidal HDL (transport mediated by ABC A1
- the dic HDL converted to mature spheres by LCAT, by esterifying it to form hydrophobic ester core. the sphere can also recieve more cholestrol from other rafts by diffusion, SRB1 and other membrane transports
- transports to liver to dispose in bile

FOAMY cells and lipid m/p give up their cholestrol to HDL (atheroma) by ABC-A1

Potential Antiatherogenic Actions of HDL

- anti-infectious
- modulat NO
- A/I

LDL in Artery Walls

1. LDL through endothelium into sub-endo space
2. chemical modification (oxidation)
3. Inflammation
4. m/p uptake
5. foam cell formation
6. inflammation INC. permeability of endothelium thus more LDL, thus VICIOUS CYCLE


a self-perpetuating vicious cycle which will progress unless risk factors are reversed

Foam Cells


How does obesity and insulin resistance cause atheroma?

Via triglyceride and CETP
1. Obesity, insulin resistance and diabetes predispose to overproduction of triglyceride rich VLDL by the liver
2. INC. VLDL enhances action of cholestrol ester transfer protein (CETP)
3. This promotes lipid transfer between TG and lipid rich particels
4. Replacement of LDL with TG and thus removal of TG by lipolysis promotes formation of small dense LDL
5. And the smae process in HDL forms small, unstable particles which are catabolised

TG and Lipoproteins

TG drives cholesterol ester transfer via CETP (> 1.5 mmol/l ?) :
1) TG exchange reduces HDL-C and impairs reverse cholesterol transport. TG and HDL-C are inversely correlated
2) TG exchange causes smaller, denser LDL. When TG is raised, LDL-C underestimates CVD risk.

3) Small, rather than large, TG-rich particles may carry cholesterol into the artery wall. The linear relationship between TG and CVD risk declines at very high levels

Ceiling effect with plasma TG

maximum cardiovascular risk occurs in moderate hypertriglyceridaemia. The risk associated with severe hypertriglyceridaemia is elevated, but not to the same extent.

Atherosclerosis: Stages and timeframe

Everyone has atherosclerosis

The rate of this progression is proportional to the number of risk factors and the severity of each individual risk factor

that factors predisposing a plaque to rupture are

- Lipid accumulation
- Increase in lipid-laden macrophages
- Disruption in reparative smooth muscle proliferation in the cap

Types of Plaque Bleeding

Total daily Fat in Diet

American Heart Association Diet. Total fat should be 30% (not the percentage weight but that by energy)

Lifestyle-Heart Hypothesis

gene -environment interaction

Atherosclerosis Risk factors

IHD Risk Factor Odds Ratio Population attributable risk
ApoB/ApoAI 3.25 49%
Smoking 2.87 36%
Hypertension 1.91 18%
Diabetes 2.37 10%

Abdominal obesity 1.12 - 1.62 20%
Psychosocial 2.67 33%
Diet (fruit & veg) 0.70 14%
Activity 0.86 12%
Alcohol (not binge) 0.91 7%

Laboratory assessment of lipids and lipoproteins.

NHDL=TC - HDL (OK non-fasting)
Measure TC, HDL and fasting TG

Total chol = VLDL + LDL + HDL

VLDL = TG/2.2 unless TG >>4

LDL in mmol/l of chol =
Total chol - HDL - TG/2.2


LDL < 2.5 mmol/l
(< 1.8 mmol/l if high risk)
HDL>1 mmol/l, TG <2.0 mmol/l

Risk Calculators

- most based on framingham population (epidemiological studies)

Reynolds Score

which includes family history and high sensitivity C- Reactive protein

Diagnose specific conditions rather than Fredrickson "Types".

What is FH?

FH is "Familial Hypercholesterolaemia"
- Co-dominant mutation of the LDL-receptor gene (or up to 5 other genes)
- The cause of metabolic and clinical consequences including precocious cardiovascular disease (CVD)

What does FH cause?

A. Metabolic
- Increased LDL,
- Reduced clearance of remnants including LDL's precursor, IDL.
- Increased Lp(a)?
- Reduced HDL?

- Premature CHD
- Premature CVD
- Aortic stenosis
- Tendon xanthomas (11%) specific?
- Corneal arcus (27%) non-specific > 40y?
- Xanthelasmas (12%) nonspecific
- No signs highly sensitive

FH accelerated CHD

12 fold RR as cf to 3 fold for smoking

Tx of Hypercholesterolaemia

Manage 2⁰ Causes
Bile Acid Resins


Antilipemic: reduces release of VLDL from liver into circulation. Lowers LDL cholesterol and triglycerides and raises HDL cholesterol. Tox: flushing, pruritus, liver dysfunction, increased risk of myopathy when combined with statins.


LDL receptor Upregulation
1. red. intracellular cholestrol
2. release of SREBPs up-regulate LDL receptor gene
3. more LDL receptors
4. INC. removal of ciculating LDL

the statin also blocks the compensatory stimulation of INC. cholestrol synthesis by SREBPs too

LDL lowering effective?

Even in "low risk"
AR <5% NNT 167
AR 5-10% NNT 67

Therapy for Hypertriglyceridaemia

1st line fibrates
fish oil requires modest doses of 4 to 6 g per day or more as these tend to reduce triglyceride with very little effect on HDL

Fibrates MOA

Fenofibrate in Type 2 DM

good in DM for microvascular impairments (lipid levels not predicting these outcomes)

Urban myths about Lipids

Suicide, depression, violent death
Brains need cholesterol from blood
Risk of cancer
Severity of side effects

The relationship between low (?LDL) cholesterol levels and the slight risk of haemorrhagic stroke is the only adverse association not attributable to intercurrent disease.

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