Lipoprotein metabolism, cardiovascular disease and obesity Flashcards
(54 cards)
What is in an atherosclerotic plaque?
> Fibrous cap
Foam cells
Necrotic core with cholesterol crystals (from macrophage death and enzyme release)
What transports cholesterol in fasting plasma (with%)?
> Chylomicrons <5% (biggest)
VLDL 13%
LDL 70%
HDL 17% (smallest)
How is cholesterol released from peripheral cells?
Cholesterol efflux (ABC A1 protein) via fatty acids
How is cholesterol transported to the liver in the blood?
SR B1 - HDL receptor on the liver- efflux of cholesterol from peripheries to liver
CETP - Cholesterol ester transport protein moves cholesterol esters and TGs between VLDL, LDL and HDL (this receptor can promote disease development by reducing HDL levels)
How is cholesterol metabolised in the liver?
Cholesterol is converted to CE using ACAT
MTP transfers lipids (incl. TG and CE) into ApoB containing lipoproteins (uncl. VLDL)
VLDLs can be broken down in the plasma to LDLs and stimulate the LDL receptor
How does cholesterol from diet and Bile get absorbed in the liver?
Jejunum: NPC1L1, - for transfer of cholesterol to liver for EHC
ABC G5/G8 transfers cholesterol back into the lumen
It is a balance between these molecules
ACAT causes esterification
Ileum: BAT transfer bile acids for EHC
What transports TG in fasting plasma (with%)?
Chylomicrons <5%
VLDL 55%
LDL 29%
HDL 11%
What are lipoproteins in order of denstiy?
Chylomicron < FFA < VLDL < LDL < IDL < HDL
What is PCSK9?
> Binds LDLR and promotes its degradation
> Loss of function mutation of PCSK9 -> low LDL
levels
> Novel form of LDL-lowering therapy is AntiPCSK9 MAb
Which lipoprotein is a CVD risk factor?
What is the treatment?
Lipoprotein(a) is a CVD RF
Tx: Nicotinic acid
What would you consider dyslipidaemia?
Hypercholesterolaemia
Hypertriglyceridaemia
Mixed hyperlipidaemia
Hypolipidaemia
Which diseases are considered primary hypercholesterolaemia and what are their mutations?
- Familial hypercholesteraemia
(type II)
> AutoDom: LDLR, apoB, PCSK9
> AutoRec: LDLRAP1 - Polygenic hypercholesteraemia
> Several polymorphisms
> incl. NPC1L1, HMGCR, CYP7A1 - Familial hyperα-lipoproteinaemia (high HDL)
> CETP deficiency - Phytosterolaemia
> ABC G5 & G8 (prevent absorption of non sterols- premature atherosclerosis)
What are the signs of high cholesterol?
> xanthelasma and tendon xanthomata
Corneal arcus
Atheromous disease
What are the types of primary hypertriglyceridaemia?
> Familial type I: lipoprotein lipase or apoC II deficiency
> Familial type IV: Increased synthesis of TG
? Cause
> Familial type V: sometimes due to apoA V deficiency
What are the types of primary hypertriglyceridaemia and their causes?
> Familial type I: lipoprotein lipase or apoC II deficiency
> Familial type IV: Increased synthesis of TG ? Cause
> Familial type V: sometimes due to apoA V deficiency
What are the types of primary mixed hyperlipidaemia?
Familial Combined hyperlipidaemia
Familial dysβlipoproteinaemia (type III) - elbow xanthoma and shiny palmar crease
Familial hepatic lipase deficiency
What are the types and causes of Hypolipidaemia?
> Aβ-lipoproteinaemia: MTP def
> Hypoβ-lipoproteinaemia: Truncated apoB protein
> Tangier Disease: HDL def (ABC AI mutations)
> Hypoα-lipoproteinaemia: apoA-I mutations (sometimes)
What are the causes of secondary hyperlipidaemia?
Hormonal factors (e.g. pregnancy, hypothyroid)
Metabolic disorders (e.g. diabetes, obesity, gout)
Renal dysfunction (e.g. nephrotic syndrome and chronic renal failure)
Obstructive liver disease (like PBC)
Toxins
Iatrogenic
Hypothyroidism
Misc.
What relationship does serum cholesterol have to CHD?
Positively correlated
How are Total Chol: HDL ratios related to CHD?
Positively (increased HDL decreases CHD risk)
How are TGs related to CHD?
Positively
What is the management of hyperlipidaemia?
> First line is always conservative – dietary
modification and exercise [although dietary
intake of cholesterol correlates poorly with
actual triglyceride levels]
> Statin therapy
> HMG-CoA reductase inhibitor
> Reduces intrinsic synthesis of cholesterol in the liver
> Side effects – myopathy/rhabdomyolysis, fatigue
> Other agents more rarely used include Ezetimibe
How do you manage obesity?
> Conservative measures
> Medical- No medication has been safely proven to provide sustained weight loss
> > Orlistat (A gut lipase inhibitor) is used however side effects of profound flatus and diarrhoea are often too cumbersome for patients to tolerate
Rimonabant (a cannabinoid antagonist) was trialled and
discontinued from use as there was an increased risk of adverse events in the form of suicide
> Surgical
> Bariatric surgery is indicated in patients with a BMI >40 or >35 with a comorbidity associated with obesity
> To be considered requires extensive screening and must commit to long term follow up usually.
What are the risks and benefits of bariatric surgery?
Benefits:
Success = > 50% ↓ in excess weight (i.e. actual – ideal)
Diabetes ↓ 72%
Serum triglyceride ↓ 50-60%
HDL cholesterol ↑13-47%
Fatty liver ↓
Hypertension ↓
Risks:
Post-op mortality 0.1-2%
