Statin Steampunks Statins

2.1 – “Statin Stea Steampunks”: mpunks”: Stat Statins ins Production & metabolism of lipo lipoproteins proteins • Lipoproteins (various vehicles) traffic cholesterol & triglycerides between the liver, intestinal tract, and peripheral tissues. • Chylomicrons o The intestines absorb exogenous lipids – free fatty acids (FFAs) & cholesterol (gold bars imprinted with sterol molecular structure)– at the luminal brush border in the small intestine (airship with processing facility with brush border cell flags and intestinal piping). After being absorbed in GI tract, lipoproteins are bound in chylomicrons (Hot air balloons). ▪ FFAs absorbed from lumen are combined with glycerol to form triglycerides, which are the main component of chylomicrons (helmeted people with 3-pronged tridents = triglycerides) ▪ Cholesterol is confined to the outside of the chylomicrons ▪ While in the in the luminal epithelial cells, cholesterol is esterified. Cholesterol esters fill the inside of the chylomicrons (packaging gold bars into chests = cholesterol esters). ▪ Apolipoprotein B48 (ApoB48) is included into the cell membrane to facilitate exocytosis into circulation. o Chylomicrons enter into lymphatic system via villi lacteals → transport along lymphatics to thoracic duct → make their way into circulation. Interact with HDL to pick up ApoE which facilitates liver uptake. o Chylomicrons deliver triglycerides from the intestine to peripheral tissues en route to the liver. ▪ LPL is attached to luminal service of capillary endothelium in extrahepatic tissues (lipo-port lighthouse). Facilitates removal of triglycerides into tissues (helmeted people reaching land by way of lighthouse) ▪ FFAs can be used for energy by heart and SKM (muscular seaweed) ▪ Alternatively, FFAs can be converted back to triglycerides & stored in adipose tissue (fatty sea foam). o Once depleted of triglycerides, chylomicron remnants are returned to the liver (central processing facility). ApoE interacts with LDL receptors (LDL-R) (Load-L Receptor flags) to transport chylomicron remnants into the liver via endocytosis (Pulling in empty E balloon and offloading chests). Cholesterol remnants will be excreted in bile acids or repackaged & put back into circulation. • At the liver o Cholesterol may be synthesized endogenously by HMG-CoA reductase (HMG Ore Processing produces gold ingots); the first intermediate in this process mevalonic acid, aka mevalonate (process is being evaluated). o Liver packages cholesterol (either endogenous or exogenous from chylomicron remnants) into VLDL (chests containing gold being packed onto VLDL zeppelins). o Synthesizes HDL. • VLDL o Synthesized in liver of cholesterol & triglycerides (triglycerides make up 60% total weight) (zeppelins). Include ApoB100 in the lipoprotein exterior (B-shaped anchors). o Deliver triglycerides to peripheral tissues ▪ VLDL is hydrolyzed by LPL, releasing FFA (helmet people entering island via lighthouse). o VLDL depleted of triglyceride forms IDL (essentially VLDL remnants). Some of the IDL particles head to the liver. Many stay in circulation where interact with HPL (not in the picture). Density increases, which is remodeled into cholesterol rich LDL particles. • LDL o Lipid rich transport proteins (little boats). Cholesteryl ester-rich core. Also include ApoB100(B-shaped anchors).. o LDL is the main source of cholesterol for all the peripheral nucleated cells in the body. Nucleated cells contain LDL-Rs which can endocytose entire LDL particles. ▪ LDLRs are upregulated by cells that need more cholesterol, downregulated when cells need less. o About 70% of LDL is removed from circulation by the liver (same mechanisms as described above). ▪ Also adrenals for hormone synthesis ▪ Those that aren’t picked up by the liver can penetrate the vascular endothelium → atherosclerosis • HDL o HDL particles contain mostly protein by weight (HG Wellsian subs). Nascent HDL is secreted by the liver & intestine. A complicated process leads to acquisition of surface apolipoproteins, including ApoE, ApoAI, ApoCII. o HDL goes on to collect cholesterol from peripheral tissues – scavenged in form of free cholesterol from tissue cell membranes (scuba scavenger loading finds onto HDL platform). Esterified by LCAT (lecithin cholesterol acetyltransferase) (load catch platforms on subs). This is the mature HDL. ▪ Women less than 50 & men <40 with low cholesterol levels are ↑risk of CVD d/t low levels of HDL o HDL also loads cholesterol esters to LDL/VLDL using CETP (cholesterol ester transfer protein) (chest transfer platform on subs). Once on the LDL, cholesterol esters are returned back to the liver. o HDL can also deliver cholesterol esters direct to the liver via scavenger 1 receptor (HDL Scavenger 1 sub) Drugs Statins (pirates) • Before initiating therapy, lifestyle modification is first line. • Indications: o Most powerful drugs for lowering LDL cholesterol – can see reduction in the range of 30-60% (sinking LDL ship) Used in treatment of hypercholesterolemia = ↑↑LDL (recall these are cholesterol laden), usually above 200 ▪ May also modestly lower triglycerides, depending on the specific medication (pirate knocking triglyceride guy off of sinking ship) ▪ Modest increase in HDL ▪ Note that statins are not the most effective drugs for lowering triglycerides or increasing HDL. o Statins are the most important lipid lowering drug for preventing future CV events (angel over yellow-filled crown). Statins are the only lipid lowering drug consistently shown to reduce the risk of atherosclerotic HD. o Standard of practice to initiate statins following any ACS, regardless of cholesterol levels (broken stringed guitar). o Used as secondary prevention in high risk conditions including: ▪ Diabetes (guy with candy jar) ▪ Peripheral artery disease (gunky red pipe) ▪ Reduce long term risk with h/o TIA or stroke TIA (painter with black stroke on hat) • Mechanisms o Inhibit HMG-CoA Reductase → ↓endogenous cholesterol production (pirate at HMG-Ore Reductase) o Hepatocytes consequently increase LDLR to take up more cholesterol → ↑LDL clearance from circulation (pirate sitting on a huge pile of gold) o Statins have extensive first pass metabolism, so act largely in liver. • Adverse effects o May be teratogenic (Class C; never been tested, so risk to fetus/baby is unclear) (tarantula painting) o can cause myopathy (bite out of drumstick) ▪ usually within weeks to months of initiating ▪ usually with proximal symmetrical muscle weakness or soreness, ± functional impairments. ▪ Some patients will have ↑CK, but not always (Chicken) o Will have mild elevations in LFTs. Usually reversible with discontinuation. If asymptomatic, do not need to monitor; however, do need baseline values (LFT flag) o All metabolized by CYP450 except pravastatin (CYP450 tank)