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Flashcards in Lipid metabolism Deck (54):

Where does most of the body's lipids come from?

80% from synthesis in the liver
20% from intake


Metabolism of lipids - transportation

- lipids are absorbed as triglycerides, packaged with cholesterol, triglycerides are dropped off with help of lipoprotein and stored in peripheral tissue. Cholesterol is taken back to liver. Cholesterol in the liver functions as a source of energy, production of bile salts, and production of cholesterol based hormones


Where can lipids go once they are in the blood as lipoproteins?

- can be excreted in feces
- synthesized from carbs and proteins
- oxidized for energy
- converted to brain and nerve tissue


What is function of lipids that are stored in the adipose tissue?

- used for insulation
- support vital organs
- generate heat
- serve as energy reserve


What are lipids and what are the 3 main categories of lipids?

- chemical substances composed of long chain fatty acids
- triglycerides
- phospholipids
- cholesterol


How are triglycerides used?

- used in energy metabolism


Function of phospholipids?

- impt structural components of lipoproteins, blood clotting components, myelin sheath and cell membranes


Function of cholesterol?

- precursor of steroid hormones
- necessary for cell membrane synthesis
- metabolic precursor of bile acids
- obtained from diet and synthesized in liver and intestinal mucosa
- elevated levelare implicated in development of atherosclerosis
- est 41 mill Americans have significantly elevated serum cholesterol levels that could contribute to MI, CVA, PVD


What are chylomicrons?

- largest of protein molecules
- synthesized in wall of small intestine
- involved in transport of dietary TGs and cholesterol that have been absorbed from the GI tract
- transfer their TG to cells of adipose and skeletal muscle tissue
- remnnant particles, which contain cholesterol are then taken up by the liver: cholesterol used in synthesis of VLDL or excreted in the bile


How is cholesterol synthesized?

- rate limiting step in cholesterol synthesis involves enzyme 3- hydroxy-3-methylglutaryl coenzyme A reductase (if enzyme inhibited than unable to produce cholesterol)
- cholesterol and other lipids are transported in circulation as a component of lipoproteins.


Importance of lipoproteins?

- because cholesterol and TGs are insoluble in plasma, they are encapsulated by special fat carrying proteins called lipoproteins
- named based on their protein content which is measured in density: because fats are less dense than proteins: as proportion of TG decreases, density increases
least dense = more TGs


Five types of lipoproteins?

- chylomicrons: formed initially when fats absorbed in intestines
- VLDL: secreted mainly by the liver
- LDL: main carrier of cholesterol
- HDL: garbage collector, in bloodstream picking up cholesterol


what determines the cholesterol level in the blood?

- combo of factors and/or secondary causes
- genetics
- age
- dietary intake of saturated fat and cholesterol
- sedentary lifestyle
- poorly controlled DM: low HDL, hyperTG
- hypothyroidism: decreased metabolic rate
- nephrotic syndrome
- obstructive liver disease: cholesterol builds up within the liver
- alcoholism: metabolic dearrangement, and liver involvement
- drug therapy (cyclosporine, glucocorticoids)


importance of VLDL's?

- the liver synthesizes VLDL and HDL
- VLDLs contain large amounts of TGs
- provide the primary pathway for transport of endogenous TG produced in the liver
- the TG content of VLDL particles initially is high and decreases progressively as a result of enzyme activity in the bloodstream
- carry TG to fat and muscle cells where TG are removed: resulting IDL fragments are enriched in cholesterol and taken to the liver and recycled to form VLDL or converted to LDL in the vascular compartment
- IDLs are the main source of LDL


Function of LDL (aka the bad cholesterol)?

- main carrier of cholesterol
- LDL is removed from circulation by either LDL receptors (70%) on hepatocytes or by non-receptor mechanisms involving scavenger cells such as macrophages
- therefore the liver plays an extremely impt role in LDL metabolism
- other non-hepatic tissues (adrenal glands, smooth muscle cells, endothelial cells, lymphoid cells) also use receptor dependent pathway to obtain cholesterol needed for membrane and hormone synthesis


The amount of LDL that is removed by scavenger pathway is directly related to what?

- directly related to plasma cholesterol level


What does the uptake of LDL by macrophages in arterial wall result in?

- accumulation of:
insoluble cholesterol esters
- formation of foam cells
- development of atherosclerosis


Function of HDL?

- good cholesterol
- synthesized in the liver
- participates in reverse transport of cholesterol, that is, carrying cholesterol from peripheral tissues back to liver
- studies show an inverse relation b/t HDL levels and development of atheroscelorsis
- HDL facilitates the clearance of cholesterol from atheromatous plaques and transports it to the liver where it may be excreted rather than used in the formation of VLDL
- also believed that HDL inhibits cellular uptake of LDL


What increases HDL levels?

- regular exercise and moderate alcohol consumption increase HDL levels


What decreases levels of HDL?

- smoking and metabolic syndrome


What are apoproteins (or apolipoproteins)?

each type of lipoprotein consists of large molecular complex of lipids combined with proteins called apoproteins
- 6 major classes
- apoproteins control the interactions and ultimate metabolic fate of lipoproteins.. regulate lipid transport and metabolism
- research findings indicate that genetic defects in apoproteins are involved in hyperlipidemia and accelerated atherosclerosis


What are the 2 sites of apoprotein synthesis?

- small intestine and liver


Atherosclerosis manifestation?

- begins with accumulation of lipoproteins (primarily LDL) within the inner layer of arterial wall
- chemical modification (particularly oxidation) of lipoproteins lead to local inflammatory reaction involving macrophages, which ingest oxidized lipoproteins and form foam cells
- accumulation of foam cells contributes to fatty lesion formation, fatty lesions over time progress to fibrous plaques
- fissures may develop in plaque, exposing the underlying tissue to platelets
- platelet adhesion, activation and aggregation lead to thrombus formation, partially or completely occluding the vessel lumen


what percentage of vessel lesion can result in occlusion?

20% lesion -> can result in occlusion because of clot forming on plaque, most of occlusion is from fibrous tissue not plaque


Lipid metabolism summary

- ingested fat passes through the stomach and continues on to duodenum where it is then emulsified by bile
- long chain Fatty acids are packaged into micelles in small intestine and the micelles are then taken up by mucosal cells and used in synthesis of chylomicrons
- Nascent (immature) chylomicrons enter the blood at the thoracic duct
- HDLs donate apoproteins to nascent chylomicrons yielding mature chylomicrons - HDLs are synthesized primarily in the liver
- LPL (lipoprotein lipase) is activated by apoprotein CII, allowing TGs in lipoprotein to be broken down
- the resultant free fatty acids and diglycerides are taken into adjacent adipose tissue cells (adipocytes) and either utilized or stored
- chylomicrons then donate apoprotein CII to HDL in bloodstrem and become chylomicron remnants
- the chylomicron remnant is then taken up by the liver
- the chylomicron remnant components are then used to synthesize nascent VLDL
- lipoprotein lipase is activated by apoprotein CII allowing TGs in lipoprotein to be broken down
- VLDL then donates Apoprotein CII to HDL in bloodstream and becomes IDL. As IDL becomes less dense through the loss of TGs they are considered LDL
- The LDL are then taken up by tissues where they are either stored or used as fuel: 95% of fat in food is digested and absorbed into adipose tissue


What is a lipoprotein?

- phospholipid + protein complex circulating in the blood


What is a apoprotein?

- provide interface b/t lipids and aqueous environment, regulate lipid transport and regulate lipoprotein metabolism


5 major classes of lipoproteins?

- all differ in size, fxn, density, and protein content


Importance of chylomicrons in lipid transport?

- exogenous transport pathway, carry TG, dietary fat, and cholesterol from gut to the liver


Importance of VLDL?

- endogenous transport pathway
- main carrier of TG (also cholesterol and cholesterol esters) from the liver to peripheral tissues


Importance of HDL in lipid transport?

carries cholesterol from peropheral tissue back to liver, inverse correlation with Coronary heart disease risk


Importance of LDL in lipid transport?

- main carrier of cholesterol from liver to peripheral tissues
- linked to coronary atherosclerosis
- elevation result from excess production or defective clearance and utilization of cholesterol


Fatty acids?

- saturated fatty acids have single bonds b/t carbon atoms , C atoms are full or saturated: most animal fat and coconut oil


Monosaturated FAs?

- contain only one double bond
- ex: olive oil (oleic acid)


Polyunsaturated FAs?

- contain 2 or more double bonds -> includes vegetable fats
- veggie oils like soybean, sunflower, corn and afflower
- fish: tuna, salmon and herring


What is ketosis the result of?

- result of liver converting fat into fatty acids and ketone bodies (which can be used for energy as alt to glucose if glucose isn't available)
- ketosis occurs when rate of formation of ketones by liver is greater than ability of tissues to oxidize them
- excess ketone bodies will decarboxylate into acetone: this occurs in starvation and when large amounts of fats are eaten in absence of carbs (low carb diets and diabetes)


What are the health risks associated with obesity?

- type 2 diabetes
- CVD: HTN and dyslipidemia (high cholesterol, low HDL, high LDL, high TGs)
- sleep breathing abnorm:
difficulty breathing, and obstructive apnea
- gallstones
- menstrual irregularity, difficulty getting pregnant
- osteoarthritis
- cancer (colon, endometrial, breast)
- mice lacking insulin receptors in adipose tissue live longer


What is an obesogenic environment?

- eat more: increased food availability, calories/person/day increased 15% since 1970
increased portion size
increased energy density: high fat foods
- do less: increased sedentary leisure time activities, decreased occupational physical activity, increased use of automobiles


What kind of hormone is ghrelin

- gutkine, made in stomach, peaks prior to meal, stimulates appetite in humans


what kind of hormone is leptin?

- an adipokine, made in adipose tissue, increased concentration and resistance in obese individuals


What kind of hormone is insulin?

- pancreakine, made at B cells in pancreas


How are lipid disorders classified?

primary and seondary


Fredrickson's classification of lipid disorders?

-type 1: excess chylomicrons , increased TGs - pancreatitis, eruptive xanthomas, lipemia retinalis
- type 11a: increased LDL, increased cholesterol - pancreatitis, CAD, tendon xanthomas, arcus cornea
- type 11 b: both increased LDL, and VLDL, increased cholesterol and TG - pancreatitis, and CAD
- type 111: remanant of VLDLand chylomicrons, increased CHolesterol and TG - pancreatitis, CAD, PVD, palmer and tuberous xanthomas
- type IV: VLDL elevated, increasd TG - premature CAD
- Type V: chylomicrons and VLDL elevated, increase in both cholesterol and TGs - pancreatitis, eruptive xanthoma, lipemia retinalis


What are the causes of secondary hyperlipidemia?

- extra hepatic obstruction
- primary bilary cirrhosis
- DM
- hypothyroidism
- alcohol
- nephrotic syndrome
- obesity
- high dose thiazide diuretic
- exogenous sex hormone
- steroids


Familial hypercholesterolemia?

- assoc. with high risk of premature CAD
- genetic defect in LDL receptor gene resulting in either absent or defective LDL receptor activity
- this increases LDL cholesterol by 2-3 folds
- 1 in 500
- causes premature CAD
- tendon xanthomas - on back of hands, knuckles, and achilles tendon
- about 70% have xanthomas by age of 30
- family screening is very impt
- aggressive Rx is required


Familial combined hyperlipidemia?

- obesity and insulin resistance are common
- accounts for 10-15% of premature MI
- corenal arcus present**
- xanthelasma present
- tendon xanthomas don't occur


Remanant particle disease?

- rare
- risk of premature CAD and PVD
- palmer xanthoma, tuberous and eruptive xanthomas
- cholesterol and TG markedly elevated


Chylomiconemia syndrome?

- characterized by massive hypertriglyceredemia
- cholesterol level may be normal
- usually occurs in pts with alcohol excess, DM, anti-retroviral therapy


How does chylomiconemia present?

- eruptive xanthomas
- hepatosplenomegaly
- lipemia retinalis
- increased risk of pancreatitis - pt will complain of intermittant abdominal pain


Desireable cholesterol level?

- below 200
- 200-239 is borderline high
- >240 high


Desireable LDL levels?

- 160 is high


RFs of high cholesterol?

- smoking
- hypertension: 140/90
- family h/o premature CAD
- age 45 in males, 55 females


Management of high cholesterol levels?

- main indication of Rx is prevention of vascular disesae
- need to exclude 2ry causes first: glucose tolerance, TFT, U&E, LFT
- diet: for at least 6months


Drugs to help lower cholesterol?

- HMG-CO A reductase inhibitors (statins)
fibrates: gemfibrocil, fenfibrate (dont use with statins: rhabdomyolysis)
- nicotinic acid
- bile acid sequestering: cholestyramine, colestipol
- cholesterol absorption inhibitors: ezetimibe, probucol (not very beneficial)