Lipid disorders and metabolic syndrome Flashcards
Transport of lipids in the blood
Fatty acids
- Bound to albumin
TG and cholesterol
- Lipoprotein complexes.
Lipoproteins
Amphiphatic complex that transports lipids in water-like fluids.
Classes
- Chylomicrons (CM)
- Very low density lipoprotein (VLDL)
- Intermediate density lipoprotein (IDL)
- Low density lipoprotein (LDL)
- High density lipoprotein (HDL)
Apo-lipoproteins
Amphipathic proteins that form lipoprotein complex by binding to lipids.
Types:
- AI
- AII
- B-100
- B-48
- CII
- CIII
- E
Apolipoprotein A1
Major component of HDL
Co-factor for Lectin cholestero-acyl-transferace (LCAT)
- Forms cholesterol esters
ApoB-100
Receptor ligand for LDL
ApoB-48
Ligand for Chylomicrons
ApoC-1
Lipoprotein lipase inhibitor
ApoC-2
Lipoprotein lipase activator
ApoE
Chylomicron remnant R ligand
- Interacts with LDL receptor on liver.
Exogenous lipid cycle.
- Lipids are absorbed in the small bowel.
- Facilitated by bile acids produced from liver. - Chylomicrons transport TG and cholesterol to peripheral tissue via lymphatic system (thoracic duct) from the gut.
- CM is broken down by lipoprotein lipase to release TG in peripheral tissue.
- TG is broken down into FA+ glycerol in tissue. - As CM loses TG, it becomes ‘CM remnant’ which is taken up by the liver via LDL-Receptor.
Endogenous lipid cycle
- Synthesis occurs when CHO available exceeds that required for energy demand.
- Liver synthesises TG and cholesterol which is exported via VLDL to peripheral tissue.
- VLDL is broken down by lipoprotein lipase which releases TG–> FA and glycerol..
- IDL is formed when TG is removed for VLDL.
- IDL taken up by liver
- IDL loses more TG to become LDL which transports cholesterol to periphery
Regulation of cholesterol synthesis
N-SREBP transcription factor in liver stimulates production of LDL-receptors.
Increases of this, decreases cholesterol synthesis?
Lipoprotein lipase
- Location
- Function
- Substrate
- Co-factor
- Regulation
Enzyme found in capillary walls that hydrolyses TG into FA and glycerol.
Substrate
- VLDL, CM
Co-factor
- Apo-CII
Allows uptake of fats into peripheral tissue like muscles and adipose tissue.
Glycerol is processed in liver to make more TG or make glucose.
Regulation
- Feeding
- Fasting
- Exercise
Hepatic lipase
- Location
- Function
- Substrate
- Regulation
Enzyme found in liver, adrenal gland.
Breaks down TG into DG and FFA.
Substrate
- IDL–> release of FFA turns it to LDL
- HDL
Regulation
- Endocrine
Healthy serum cholesterol levels
5 mmol/L
After 5, risk of CHD doubles at least.
Healthy fasting serum TG levels
1.7 mmol/L
Serum HDL-C, healthy levels
Men
- >0.9
Women
- >1.2
HDL levels inversely correlates with heart disease risk
Familial hypercholesterolaemia
- Genetics
- Prevalence
- Signs and symptoms
Type of primary dyslipidaemia
Genetics - Autosomal dominant - Genes mutated: APOB (binds to LDL-R), PCSK9 (degrades LDL-R), LDL-R Prevalence - 1 in 200
Signs
- Raised cholesterol, especially LDL
- Tendon and skin xanthoma
- Xanthalamsa/ corneal arcus.
Secondary causes of hypertriglyceridaemia
- Obesity
- DM
- Gout
- Renal failure
- Drugs: Thiazides, beta-blockers, retionic acid, oestrogens.
- Excess alcohol consumption
Metabolic syndrome
- Features
- Classification
Reduced glucose tolerance
Hyperinsulinaemia
Hypertension
Visceral obesity
Haemostatic disroders
Dyslipidaemia: raised TG, LDL-C, low HDL-C.
Classification
- Waist circumference
>96cm Men
>80cm women
\+ any 2 - Fasting serum TG >1.7 - Serum HDL-C <1.03 men <1.29 women - BP > 130/85 - Fasting glucose >5.6mmol/L
Risk factors in framingham risk score
Age
Total serum cholesterol/ HDL-C
Systolic BP
Smoking
Sex
LVHT
T2 DM
Statins
- Lipid effects
- Mode of action
Reduces LDL by 60%
Inhibits HMG CoA reductase
Bile acid sequestrants
- Lipid effects
- Mode of action
Reduces LDL by 25%
Binds bile salts= less fats absorbed
Ezetimibe
- Lipid effects
- Mode of action
Reduces LDL by 20%
Blocks cholesterol absorption
PCSK inhibitors
- Lipid effects
- Mode of action
Reduces LDL by 50%
- Blocks LDL-R breakdwon
Fibrates
- Lipid effects
- Mode of action
Reduces TG by 35%, LDL by 20%
- Stimulates LPL
Fisk oil
- Lipid effects
- Mode of action
Reduces TG by 25%
- Reduces hepatic synthesis of TG
Lipoprotein a
- Structure
- Elevated levels
Consists of
- LDL
- ApoB
- Apo(a)
When elevated= increased CVD risk
- Prothrombotic/ anti-fibrinolytic
- Plasminogen and plasmin structural effects but no fibrinolytic activity
- Initimal deposition of Lipo(a), accelerates artherogenesis
