Lecture 11- Lipid metabolism Flashcards
fatty acids
most energy rich molecule, possible endocrine function
triglycerides
transport and storage vehicle for FA’s from place to another
phospholipids
structural basis of membranes, intracellular signalling
sterols
regulation of membrane fluidity, some play endocrine function (hormones)
cholesteryl esters
transport and storage vehicle for cholesterol
prostaglandins
intracellular signalling, endocrine function
vitamins
cofactors for different enzymes
how do lipids move?
they are insoluble in water
- bound by an apolipoprotein to form a lipoprotein complex in order to move inside or in between cells in a complex
lipoprotein complex
lipid and apolipoprotein
LDL
low density cholesterol- bad
- moves cholesterol into cell
HDL
high density cholesterol- good
- moves cholesterol out of cell
process of lipid metabolism
lipids from diet–>intestine absorbs lipids, TG’s, cholesterol and packages in chylomicrons–>TG’s can be hydrolysed, release FA’s–>liver takes up some where they catabolise and release VLDL gradually–>VLDL release FA’s becomes LDL (less TG’s but lots of cholesterol)–>cholesterol taken up by cells, most goes back to liver through reverse cholesterol transport–>impaired then cholesterol accumulates in plasma
chylomicrons
lipoprotein particles consisting of TGs, phospholipids, cholesterol, proteins
-rich in energy
reverse cholesterol transport
HDL takes excess cholesterol back from peripheral cells via ABCA1 transporter
hypercholesterolemia
cholesterol accumulates in plasma
ABCA1 transporter
cholesterol efflux to HDL which takes cholesterol back to liver
tangier disease
impaired reverse cholesterol transport
- mutation in ABCA1 transporter
- increased risk of CHD, lipid deposits
mutation in ABCA1 transporter
tangier disease- impaired reverse cholesterol transport
atherosclerosis
accumulation of cholesterol in vessel wall of artery–>plaque grows, obstructs 95% of vessel to feel symptoms—>necrosis
rupturing of atherosclerotic plaque
ruptures–>become thrombogenic, form thrombin which can detach and travel to smaller vessels and block them–> they will get no oxygen and area dies
elements of atherosclerosis
accumulation of macrophages into vessels wall, loading macrophages with cholesterol (cant get out)–>foam cells
- modification of SMC, less contractile, synthesise ECM, accumulates
- necrosis
foam cells
hallmark of atherosclerosis
- macrophages fully filled with cholesterol esters in vesicles (difficult to get rid of)
balancing act mechanisms
- cell regulates own cholesterol level- reduces cholesterol biosynthesis and LDL uptake; but only so far
- cholesterol efflux- removes cholesterol through reverse cholesterol transport
- macrophages synthesise cholesterol esters in vesicles
familial hypercholesterolemia
mutation of gene for LDL receptor- dominant trait
consequences of familial hypercholesterolemia
LDL not cleared, stays in plasma, gets modified, elevated plasma LDL, abnormal cholesterol deposition
heterozygous for LDL receptor mutation
1 in 200
- uptake of LDL by liver is slowed
homozygous for LDL receptor mutation
1 in a million
-no LDL uptake, 100% fatal, multiple MI in childhood
statins
act on level of liver, reduce amount of cholesterol in liver
- competitive inhibitors of HMG CoA reductase (inhibits cholesterol biosynthesis)
- liver thinks cells dont have enough cholesterol, upregulate LDL receptors in liver due to limited supply of endogenous cholesterol
- decrease plasma LDL cholesterol levels up to 40%
- reduces coronary events by 34%
HMG CoA reductase
produces cholesterol
PCSK9
binds to LDL-R, causes degradation of both PCSK9 and LDL-R inside endosome–>therefore less LDL-R at cell surface
PCSK9 inhibitors
stop binding of PCSK9 to LDL-R
- therefore LDL-R releases cholesterol inside endosome
- LDL-R recycles back to surface, can uptake more LDL
- decreases plasma LDL-C levels up to 70%
North Karelia Project
incidence of death by heart disease higher than anywhere else
- change diet, stop smoking, hypertension reduced
- CVD mortality decreased by 73%
Alzheimer’s disease and cholesterol
misfolding of proteins (Abeta and tau) occurs in lipid rafts
- number of rafts in brain higher than anywhere else
- abundance of rafts depends on cholesterol content
- AD may be consequence of impairment of cholesterol metabolism in brain
lipid rafts
part of plasma membrane that is rich in cholesterol and solid- proteins (Abeta, tau) that get there do not dissociate apart
criteria for metabolic syndrome
waist circumference, elevated TG’s, low HDL-C, high blood pressure, serum glucose
aetiology for obesity
increase in adipose tissue (rich in TGs)–>release FA’s–>effective energy source, so cell doesnt use glucose–>shut downs glucose transport–>glucose concentration in plasma goes up–>pancreas think that cells dont have enough insulin–>produces more insulin–>cells shut down insulin receptors–>hyperinsulinemia–>pancreatic Beta cells stress and damage–>hyperglycemia
hyperinsulinemia
excess levels of insulin in blood compared to glucose
hyperglycemia
excess glucose in bloodstream
lifestyle treatment for low HDL
clinical outcomes are certain but not sure whether benefits are caused by raising HDL
drug treatment for low HDL
increase HDL but clinical outcomes of treatment are uncertain
CETP inhibitors
inhibits CETP (changes mature HDL into VLDL-LDL)
CETP inhibitors consequences
increases HDL-C by 50-100%
- thought it would reduce CVD by 40-50%
- first CETP inhibitor completely ineffective,increased HDL-C but did not reduce CVD
- how to make raising HDL a good thing?
3 major ways we release energy
basal metabolism (60-75%) thermogenesis (10%) physical activity (15-30%)
evolutionary view of energy balance
issue of insufficient food- left to individual
excessive food- resolved on population level
lipostatic model
restoration of weight to set point
mechanism of energy balance
diet–>adipose tissue goes down (biggest producer of leptin- make you feel full)–>reduced leptin–>leptin receptor in brain signals not enough food so increase food uptake–>insulin receptors say reduce energy expenditure
- NPY/AgRP- stimulates appetite
Melanocortin- decrease appetite
weight loss
reduction in core body temperature
reduced sympathetic tone
reduced thyroid function T3/4
perception of fullness, consumption, taste altered
20% increase in muscular efficiency, fat burning
obesity paradox
people with high BMI survived longer
possible reasons for obesity paradox
fitness vs fatness
BMI vs adiposity
action bias (what you do after you got sick)
treatment bias (obese patients receive treatment)
duration bias (studies were short term)
selection bias
