• Glucose and amino acids are absorbed from the small intestine and transported into the liver via hepatic portal vein
• Many drugs are also taken into the liver via hepatic portal vein and detoxified (first-pass metabolism)

1. Apoprotein
2. Monolayer of phospholipid and cholesterol
3. Core: cholesteryl esters and some triacylglycerols

• Primarily involved in the transport of dietary lipids from the gut to the adipose tissue and liver
• Emulsified lipids by the bile acids are combined with proteins to form chylomicrons in the gut wall
• Chylomicrons are secreted into the circulation
• Chylomicrons receive apoproteins C and E from HDL
• Deliver triglycerides to adipose tissue via the action of lipoprotein lipase located in the vascular endothelial cells
• Chylomicrons are converted to a cholesterol-rich chylomicron remnants
• Transports cholesterol to the liver

• Golgi bodies in the liver form VLDL from TG, cholesterol, and protein
• Secrete the VLDL into the systemic circulation
• VLDL receive apoproteins C and E from HDL
• The VLDL deliver TG to adipose tissue
• The VLDL are transformed into IDL and LDL that contains high percentage of cholesterol
• The LDL transports cholesterol to peripheral tissues for incorporation into cell membranes and steroids
• LDL undergo endocytosis and incorporated into lysosomes
• LDL can deliver cholesterol to nascent atheromas

• Small lipoproteins that are secreted by the gut and liver
• Nascent HDL contain protein and a small quantity of phospholipid, with relatively little cholesterol or TG
• Their high density is caused by the large ratio of protein to lipid
• HDL exchange apoproteins C and E with chylomicrons and VLDL
• HDL acquire cholesterol from peripheral tissues and atheromas
• Cholesteryl esters either are transported by HDL to the liver or are transferred to LDL for transports to the liver

• Familial hypercholesterolemia; defects in LDL receptor
• Familial defective apoB100; mutations in apoB100 protein lead to decreased affinity of the LDL particles for LDL receptors

• Familial hypertriglyceridemia of unknown genetic cause; increased hepatic TG synthesis, decreased lipolysis of chylomicron and VLDL
  Familial LPL deficiency; elevated chylomicrons during infancy and impaired removal of VLDL later in life
• ApoCII deficiency; defect in ApoCII --> ApoCII is an apolipoprotein responsible for the activation of LPL

• Hypercholesterolemia and hypertriglyceridemia characterized by increased LDL (cholesterol) and VLDL (triglyceride)
• Familial combined hyperlipidemia; present features of metabolic syndrome including abdominal obesity, glucose intolerance, and HTN

1. ATP binding cassette protein AI (ABC_A1) defect
   
2. Lecithin cholesterol acyltransferase (LCAT) deficieincy
3. ApoAI deficiency
4. Cholesterylester transfer protein (CETP) deficiency

ABCA1: a cholesterol efflux pump

LCAT: converts cholesterol into cholesteryl ester

ApoAI: a cofactor for LCAT

CETP: facilitates transport of cholesteryl esters and triglycerides between lipoproteins

• Commonly caused by the presence of alcoholism, diabetes mellitus, or uremia or by the use of drugs such as beta-blockers, oral contraceptives, or thiazide diuretics
• Less commonly caused by hypothyroidism, nephrotic syndrome, or obstructive liver disease

• HMG-CoA Reductase normally converts HMG-CoA to mevalonic acid
• Atorvastatin and other drugs reduce hepatic cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase
• This increases the number of hepatic LDL receptors and enables more LDL to be delivered to the liver --> reduces the level of LDL in the plasma and the amount of cholesterol available for the formation of VLDL
• The reductase inhibitors also reduce plasma triglyceride levels (slightly)

Well tolerated by most patients

1. May cause serious and life-threatening toxicity in small percentage of people (rhabdomyolysis)

• Myalgia: muscle ache or weakness (reversible)
• Myositis: muscle inflammation accompanied by muscle pain, elevated creatinine kinase levels
• Rhabdomyolysis: muscle cells are destroyed, released myoglobin into circulation, myoglobin accumulates in kidney, can cause acute renal failure, can lead to death

2.  GI upset: including nausea, vomiting, abdominal pain, diarrhea

1. Can interact with other drugs that are metabolized by cytochrome P450
2. Cause slight increase in plasma levels of warfarin
3. Increase risk of myopathies when taken with erythromycin, gemfibrozil, or niacin

• Most of the reductase inhibitors are taken in the evening or at bedtime in order to inhibit nocturnal cholesterol biosynthesis
• Lovastatin should be taken with the evening meal to facilitate its absorption
• Atorvastatin and Rosuvastatin have longer half-lives and can be taken at any time of the day
• Lovastatin and simvastatin cross the BBB and can cause sleep disturbances
• Fluvastatin appears to be less likely to cause myopathy than other reductase inhibitors

1. Atherosclerosis
2. Hypercholesterolemia
3. Hypertriglyceridemia
4. Myocardial Infarction Prophylaxis

Cholic acid, chenodeoxycholic acid, deoxycholic acid

1. Eliminates cholesterol from the body
2. Eliminates catabolites from the body
3. Emulsify lipids and fat-soluble vitamins in the intestine

• After the resins (anion exchange) bind to bile acids, the bile acid-resin complex is excreted
• This action prevents the enterohepatic cycling of bile acids and facilitate the liver to synthesize bile acids from cholesterol
• The liver increases the number of LDL receptors --> results in the reduction in the levels of LDL in the serum
• The resins have relatively little effect on the levels of HDL and TG

1. Constipation, fecal impaction, and other GI side effects
2. Can cause irritation of the perianal area and a skin rash

• In the gut, cholestyramine and colestipol can bind to digoxin, thyroxin, warfarin, and other drugs
• For this reason, it is best to take these resins 2 hours before or after taking other medications
• A newer resin, colesevelam, does not affect the oral bioavailability of digoxin, warfarin, or lovastatin
• Colesevelam can be co-administered with most drugs including HMG-CoA reductase inhibitors

• Bile acid resins are moderately effective drugs for hypercholesterolemia with an excellent safety record
• Especially valuable for patients who are young requiring prolonged drug therapy
• Cholestyramine and colestipol are available in powder form for mixing with water or juice just before administration
• Colesevelam is a newer resin that is available as solid tablets (more convenient and palatable)

1. Diarrhea
2. Hypercholesterolemia
3. Digoxin overdose (colestipol)

Colesevelam is mainly used to treat hypercholesterolemia

• Inhibits the absorption of dietary cholesterol by blocking cholesterol/sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1) at the brush border of the small intestines
• Cholesterol absorption is reduced by about 50%
• It has no effect on the absorption of TG, bile acids, or fat-soluble vitamins
• Given alone, ezetimibe reduces plasma total cholesterol by about 15% and LDL cholesterol by about 18%
• When taken with a low dose statin, the combination is as effective as the highest statin doses

1. Diarrhea
2. Headache
3. Angioedema

• Activates a gene transcription factor, peroxisome proliferator-activated receptor alpha (PPAR-alpha)

1. Increased expression of LPL -> lower plasma TG levels
2. Decreased expression of an inhibitor of LPL, apolipoprotein C-III
3. Increased expression of enzymes that oxidize FA
4. Increased expression of apoproteins A-I and A-II; increase HDL levels
5. Increased expression of cholesterol transport protein
6. Increased expression of hepatic LDL receptors

• The fibrates reduce plasma levels of VLDL, TGs, and LDL-C, while raising levels of HDL-C

1. Can cause blood cell deficiencies and other hypersensitivity reactions
2. Rhabdomyolysis and other myopathies
3. GI upset
4. Rash or pruritis
5. Dizziness, headache

• The combination of HMG-CoA Reductase Inhibitors and fibrates should be avoided or used with great caution
• Fibrates can be given with cholestyramine and colestipol but the doses must be separated by more than 2 hours, because these resins reduce fibrate absorption

1. Hyperlipoproteinemia
2. Hypertriglyceridemia

• Reduce lipolysis and free fatty acid mobilization from adipocytes to the liver
• Act at a high-affinity inhibitory G protein-coupled membrane receptor (decreases cAMP)
• Decrease FFA availability reduces hepatic TG synthesis and VLDL secretion from the liver

1. the large doses of niacin required to lower serum lipid levels sometimes produces marked vasodilation and flushing of the skin
2. Elevates serum transaminase levels and cause hepatitis
3. Produces gastric distress and may activate peptic ulcer
4. Can cause glucose intolerance in some patients and can aggravate diabetes mellitus
5. Niacin should be avoided in patients with hepatic disorders, peptic ulcers, or diabetes mellitus

• Niacin is the best agent available for increasing HDL-C  (increments of 30-40%)
• Lower TGs by 35-45%
• Reduces LDL-C levels by 20-30%

1. Hypertriglyceridemia
2. Nutritional Supplementation (lower doses)

Fish Oil, Omega-3 Fatty Acid

• reduces TG in plasma, increase conversion of VLDL to LDL, increase HDL
• reduction of plasma fibrinogen; decreases thrombogenesis
• blocks platelet aggregation
• retards atherosclerosis by reduced expression of endothelial adhesion molecules
• promotes NO-mediated vasodilation
• reduces arrhythmias