Chempath - Lipids Flashcards
Plasma lipoproteins from big to small
Chylomicrons, FFA, VLDL, IDL, LDL, HDL
Cholesterol transport in fasting plasma
Chylomicrons - 5%
VLDL - 13%
LDL - 70%
HDL - 17%
Cholesterol Metabolism (might be good to look at this with diagram from lec)
Cholesterol in gut from diet and bile – solubleised in mixed micelles (major component of bile acids)
Cholesterol transported across the brush border by NPC1L1 into the lymphatics and liver.
Balance between this and ABC G5/ABC G8 (causes it to go back into lumen) which determines net amount of cholesterol that is absorbed.
Bile acids reabsorbed in terminal ileum
When cholesterol gets to the liver, it downregulates the activity of HMG-CoA reductase (main enzyme involved in cholesterol synthesis from acetate and MVA) – efficient absorbers of cholesterol will have low rates of cholesterol synthesis and vice versa
Cholesterol (from gut or liver) – hydrolysed by 7a hydroxylase into bile acids OR becomes esterified by ACAT to become cholesterol ester
Cholesterol ester + triglyceride + apoB –> incorporated into VLDL (transfer protein MTP important in this packaging process)
VLDL is main precursor of LDL. LDL then circulates in plasma for 3-4 days before being taken up by receptors on the liver surface (LDL-R).
LDL transports lipids from liver to periphery –> deliver it to cells that have LDL receptors other than the liver
HDL – transports excess lipids from the periphery (ABCA1 important in this process: mediates the movement of free cholesterol from the peripheral cells to the HDL)
CETP (cholesterol ester transfer protein) – mediates movement of cholesterol ester from HDL to VLDL, and of triglyceride from VLDL to HDL
Once this is completed, some of the HDL cholesterol ester is taken up by the SR-B1 receptor on the liver
Triglyceride transport in fasting plasma
Chylomicrons - <5%
VLDL - 55%
LDL - 29%
HDL - 11%
Triglyceride Transport and Metabolism (look at diagram)
Chylomicrons have short HL in plasma
VLDL main transporter of cholesterol in the fasted state
Trigs absorbed in the small intestine
Get hydrolysed into FFAs then resynthesized into trigylcerides and transported via chylomicorns into the plasma
Chylomicrons hydrolysed by lipoprotein lipase (in capillaries, particularly in muscles) into FFAs
These FFAs are partly taken up by the liver and resynthesized into trigs and exports them as VLDL (or go to adipose tissue)
VLDL acted on my lipoprotein lipase and hydrolysed IDL /FFA
Primary hypercholesterolaemia
Familial hypercholesterolaemia (type II): dominant mutations of LDL receptor, apoB or PCSK9 genes. Rarely, autosomal recessive inheritance (LDLRAP1).
Polygenic hypercholesterolaemia: Multiple loci including NPC1L1, HMGCR, CYP7A1 polymorphisms
Familial hyperαlipoproteinaemia: sometimes CETP deficiency
Phytosterolaemia: mutations of ABC G5 & G8 (photo = plant sterols, usually these are returned to the lumen in the small intestine)
Normal uptake of LDL
LDL binds to receptors in coated pits (1) and subsequently undergoes endocytosis (2). Taken up in lysosomes for further processing.
Homozygous Familial Hypercholesterolaemia
Rare - 1 in a million
Corneal arcus in young children
LDL 10x normal
Untreated - death before 20 due to atherosclerosis of the aortic root –> acute coronary insufficiency
Heterozygous Familial Hypercholesterolaemia
Much more common - 1 in 500
Corneal arcus
Xanthelasma
Tendon xanthoma - achilles
Proprotein convertase subtilisin/kexin type 9 (PCSK9) mutation as a cause of familial hypercholesterolaemia
Function is to bind to LDL receptor and promote its degradation.
Rarely FH is caused by dominantly-inherited gain of function mutations of PCSK9, which increase rate of degradation of LDL receptors. –> fewer on surface of the liver therefore less LDL being bound and degraded
Loss of function mutations of PCSK9 are associated with low LDL levels.
Primary Hypertrigylceridaemia
Familial type I: lipoprotein lipase or apoC II deficiency. Can see chylomicrons in plasma if you leave it to sit - creamy layer. Eruptive xanthomas.
Familial type IV: Increased synthesis of TG? Cause. Can see VLDL in plasma.
Familial type V: sometimes due to apoA V deficiency. More severe version of 4. Can see both chylomicron and VLDL layers in fridge test.
Primary Mixed Hyperlidiaemia
Familial combined hyperlipidaemia: ? cause - in a family some people will have high cholesterol and some will have high triglycerides
Familial hepatic lipase deficiency
Familial dysβlipoproteinaemia (type III) - quite uncommon, aberrant form of ApoeE (2/2) - homozygous. If you have ApoeE4/4 - increased risk of alzheimer's x10. ApoE3/3 is normal. Palmar striae (lipid deposits in palmar crease) - diagnostic of type 3. Can also get eruptive xanthomas.
Nephrotic Syndrome
Loss of albumin increases cholesterol synthesis
Primary biliary cirrhosis can present with
Gross xanthelasma
Hypolipidaemia
Aβ-lipoproteinaemia: MTP deficiency (recessive)
Hypoβ-lipoproteinaemia: truncated apoB (dominant)
Tangier disease: HDL deficiency caused by ABC AI mutations
Hypoα-lipoproteinaemia: sometimes due to apoA-I mutations