Metabolism of Lipids - Dr. Ortiz - 2024-01.pdf

Metabolism of Lipids: By: Sergio R. Ortiz, MD MPH, CPH Objectives: • Review the metabolism of lipids (digestion & absorption) • Recognize the importance of lipoproteins & identify structural differences. • Know the metabolic pathways (including enzymes and receptors) for each lipoprotein. Lipid...

Metabolism of Lipids: By: Sergio R. Ortiz, MD MPH, CPH Objectives: • Review the metabolism of lipids (digestion & absorption) • Recognize the importance of lipoproteins & identify structural differences. • Know the metabolic pathways (including enzymes and receptors) for each lipoprotein. Lipid Metabolism: • Lipids are essential to the structure and maintenance of living cells. • They serve as structural components of membranes, the major source of energy, and precursors to a variety of specialized regulatory molecules, such as steroid hormones, prostaglandins and leukotrienes. Lipids in the human diet consist mainly of Triacylglycerides, Phospholipids, Sphingolipids, Cholesterol, Free and Cholesterol esters, Waxes and lipid-soluble vitamins. Lipid Metabolism: The metabolism of lipids involves several steps: TAG: triacylglyceride Lipid Digestion: •Completed in the intestinal lumen, where large emulsions of fat globules are mixed with bile salts and pancreatic lipid digestive enzymes •Formation of aqueous suspension of small fatty droplets to maximize exposure to the pancreatic lipases for lipid hydrolysis. •Formation of mixed micelles that provide a continuous source of digested dietary products for absorption at the brush-border membranes of the enterocytes. Monoacylglycerol, diacylglycerol and free fatty acids+ bile salts, cholesterol, lysophosphatidic acid and fat-soluble vitamins. Mixed Micelles FORMED OF à monoglycerides, fatty acids, bile salts and phospholipids + fat soluble vitamins and cholesterol. ü Micelles are about 200 times SMALLER than emulsion droplets. ü FUNCTION à Transport the poorly soluble monoglycerides and fatty acids to the surface of the enterocyte where they can be absorbed. ü Micelles are constantly breaking down and re-forming, feeding a small pool of monoglycerides and fatty acids to enterocytes. ü Because of their nonpolar nature, monoglycerides and fatty acids can just diffuse across the plasma membrane of the enterocyte. Some absorption may be facilitated by specific transport proteins. Only freely dissolved monoglycerides and fatty acids can be absorbed, NOT the micelles. FA-binding protein (IFABP), CD36 and FA-transport protein-4 (FATP4). Lipid Digestion 1. FAs and MAG enter the enterocytes by transporters, such as intestinal FA-binding protein (IFABP), CD36 and FA-transport protein-4 (FATP4). 2. They are then re-esterified sequentially inside the endoplasmic reticulum by MAG acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT) to form TAG. 3. Phospholipids from the diet as well as bile, mainly LPA, are acylated by 1-acyl-glycerol-3-phosphate acyltransferase (AGPAT) to form phosphatidic acid (PA), which is also converted into TAG. 4. Dietary CL is acylated by acyl-CoA:cholesterol acyltransferase (ACAT) to cholesterol esters (CE). 3 1 2 4 5 5. Facilitated by microsomal triglyceride transfer protein (MTP), TAG joins CE and apolipoprotein B (ApoB) to form CHYLOMICRONS (CM) that enter circulation through the lymph. Triacylglycerol (TAG); phospholipids (PLs); cholesterol (CL); fatty acids (FAs) bile salts (BS); monoacylglycerol (MAG); diacylglycerol (DAG); lysophosphatidic acid (LPA) Lipoproteins Lipoproteins are particles found in plasma, composed of proteins and various classes of lipids. OBJECTIVE à transport of hydrophobic lipids in the aqueous environment of the plasma. • Distribution of triacylglycerols and cholesterol between the intestine, liver, and peripheral tissues. • Transport of triacylglycerols is linked to body fuel metabolism, whereas the transported cholesterol forms an extracellular pool available to cells. Triacylglycerols are transported in plasma within lipoprotein particles, whereas short- and medium-chain fatty acids are transported bound to albumin. Lipoproteins consist of: •A core of TGs, cholesteryl esters (CE) and lipid-soluble vitamins. •A monolayer membrane of PLs and small amounts of free cholesterol. •Proteins called “Apoprotein” which may be “integral” apoproteins (apoA or apoB) penetrating as a transmembrane protein through the lipid monolayer or “peripheral” apoproteins (apoC or apoE) that are on the outer surface of the phospholipid membrane. Metabolism of Lipoproteins Lipoproteins There are 5 distinct lipoproteins: 1. Chylomicrons 2. VLDL (very low density lipoproteins) 3. IDL (intermediate density lipoproteins) 4. LDL (low density lipoproteins) 5. HDL (high density lipoproteins) Each lipoprotein contains a specific amount of protein, triglyceride, phospholipids, cholesterol and cholesterol esters. Lipoproteins There are many different types of Apolipoproteins that have different functions and are associated with the different lipoproteins: Chylomicrons •Chylomicrons (CM) are the transporters of dietary lipids (exogenous) to adipose tissue and the liver. •Our intestines package lipids, and vitamins into CM in the enterocyte cell lining the small intestine. •Apoprotein à apoB-48 •“integral” apoprotein (transmembrane protein) and is a shortened form of apoB-100. •Large molecule with phospholipid and cholesterol monolayer with apoB-48 and in the core mostly triglycerides. APOB gene The APOB gene provides instructions for making two versions of the apolipoprotein B protein, a short version called apolipoprotein B-48 and a longer version known as apolipoprotein B-100. In intestinal cells, RNA editing converts a cytosine C to an adenosine A, producing the stop codon UAA. Consequently, the apoB of intestinal cells (apoB-48) contains only 2,152 amino acids. ApoB-48 is 48% of the size of ApoB-100. Chylomicrons metabolism They enter the lymphatic circulation and make their way via the thoracic lymph duct to the circulation where the duct empties into the subclavian vein in the neck. In the liver the hepatocytes binds the apoE on chylomicrons via the LDL receptor (LDL-R) on the surface of the hepatocytes and the chylomicron is taken into the liver cell where the triglycerides will be used in metabolism. In the blood, chylomicrons acqu ire two new peripheral apoproteins: apoCII and apoE. The chylomicrons travel either to the liver or adipose tissue The chylomicron will also bind to adipocytes via the apoCII to lipoprotein lipase (LPL) an enzyme on the surface of the adipocyte. When triglyceride is reduced to ~20% in the chylomicron the apoCII dissociates from the chylomicronà apoB48 and apoE “chylomicron remnant”. The LPL cleaves the triglycerides in the chylomicron and the glycerol and free fatty acids enter the adipocyte thus depleting the chylomicron of triglyceride content and filling the fat cell with fatty acids. The chylomicron remnant is cleared from the circulation by the liver cell (hepatocytes) via the chylomicron remnant receptor on the hepatocytes, binding to the apoE on the remnant particle. The liver then makes use of the remaining triglyceride. Lipoprotein lipase (LPL) • Lipoprotein lipase (LPL) catalyze the hydrolysis of the triglycerides to form free fatty acids (FFA) from chylomicrons and VLDL. • ApoC-II on the lipoprotein serves as a cofactor for LPL. Lipoprotein lipase (LPL) Role of LPL in various tissues. Muscle: Energy provision WAT: Storage of TGs Lactating breast: Milk TGs synthesis • More than 220 mutations in the LPL gene have been found to cause familial lipoprotein lipase deficiency. • The most common mutation replaces the glycine with acid glutamic acid at position 188 in the enzyme (Gly188Glu or G188E). • Mutations in the LPL gene reduce or eliminate the activity of lipoprotein lipase, preventing the removing TGs from chylomicrons. • RESULTà fat-laden chylomicrons accumulate in the blood, leading to abdominal pain and the other signs and symptoms. (recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly.) • Clinical diet and medication are needed to control the symptoms. VLDL Metabolism VLDLs carrying TGs, PLs and cholesterol esters from the liver to other tissues throughout the body. It contains one apoB-100 integral apoprotein in the monolayer membrane. ü VLDL are made by the liver ü Transport lipids to other tissues especially adipose tissue. The VLDL passes into the blood stream and like CMs acquires two further apoCII and apoE surface apoproteins from HDL molecules. VLDL Metabolism LDL retains a single major protein, apoB100, and is removed from circulation by the apoB/E receptor. In the capillaries of adipocytes, VLDL binds LPL via the apoC-II with the enzyme cleaving the TGs to glycerol and fatty acids to be used by the adipocyte. LPL acts on VLDL to produce intermediatedensity lipoproteins (IDL), which can be taken up by B-100, Ereceptor, or further lipolyzed, to produce LDL. LDL Metabolism Although most tissues make their own cholesterol, the liver provides some cholesterol through the VLDL remnant-LDL cascade. • Circulating LDL binds to the LDL receptor (LDLr) found in many tissues. • The entire LDL is then degraded, providing the cell with cholesterol. Many LDL particles bind to liver LDLr, thereby closing a futile cholesterol cycle: (Liver → VLDL → LDL → Liver) LDL is the major cholesterol carrier in human blood. LDL Receptor Brown and Goldstein (1986) identified the LDLR in their search for the origin of the genetic disease FAMILIAL HYPERCHOLESTEROLEMIA (FH) • Severely elevated LDL cholesterol (LDL-C) levelsà atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age • INCREASED RISK FOR CARDIOVASCULAR DISEASE. • Xanthomas (patches of yellowish cholesterol buildup) LDL Receptor mediated endocytosis LDL and Lp(a) •LDL can complex with apo(a) protein to form Lp(a) particles, which appear particularly atherogenic. •High plasma concentrations of Lp(a) are a risk factor for coronary heart disease (CHD) in particular in patients with concomitant elevation of LDL. •Lp(a) is structurally similar to LDLs containing an apoB-100 surface protein with an additional apo(a) •prothrombotic capabilities in addition to potential atherogenicity. •The apo(a) found on Lp(a) is structurally related to plasminogen, as both contain a protease domain and multiple kringles. •This structural similarity allows apo(a) to inhibit plasminogen activation, potentially leading to a tendency for thrombosis, a process known to play a role in acute cardiac events. HDL Metabolism HDL particles remove cholesterol from cells (Reverse cholesterol transport). • The HDL are assembled in the liver and the intestine. • Apolipoproteins à apoAI and apoAII mainly & in les quantity apoC and apoE. • HDL acquire cholesterol from peripheral cells and either transport it by a direct route to the liver or indirectly transfer it to triglyceride-rich particles, chylomicrons, VLDL, or LDL, where they follow the remnant/LDL route HDL Metabolism •The HDL are formed as discoid, lipid-poor particles (pre-β-HDL) that contain mainly apoAI. •They are partly constructed from the excess phospholipids shed from the VLDL during their hydrolysis by LPL. •They accept cholesterol from cells through the action of a membrane ATP-binding cassette transporter A1 (ABCA1). ABCA1 uses ATP as a source of energy and is rate-limiting for the efflux of free cholesterol to apoAI. The free cholesterol acquired by the nascent HDL is esterified by lecithin cholesterol acyltransferase (LCAT). • Cholesteryl esters move into the interior of the particle, which enlarges and becomes spherical - it is now designated HDL-3. • Aided by the CETP (cholesteryl ester transfer protein), it transfers some of its cholesteryl esters to chylomicrons, VLDL, and remnant particles in exchange for triglycerides. • Acquisition of triglycerides enlarges the particle further - it now becomes HDL-2. • This exchange route seems to be the principal pathway of reverse cholesterol transport in humans. HDL Metabolism • HDL-3 particles bind to the scavenger receptor BI on the hepatocyte membrane and transfer CEs to the liver. • When the transfer is completed, the size of the HDL particle decreases again. • Some of the redundant surface material is released, forming apoAIrich, lipid-poor pre-β-HDL, which reenter the cholesterol-removal cycle. Reverse cholesterol transport CEs, cholesteryl esters; LCAT, lecithin cholesterol acyltransferase; CETP, cholesterol ester transfer protein; HTGL, hepatic triglyceride lipase. Question: A 40-year-old female patient arrives to your consult because since she was young, she has been having yellow lumps on the skin of her face and hands. She has never been to a doctor before for checkup. You explore her and diagnose the lumps as xanthomas. Suspecting there are abnormalities in a receptor of a lipoprotein causing this symptoms. Which lipoprotein receptor is most likely affected in this patient? a. b. c. d. e. HDL receptor Apoprotein LDL receptor VLDL receptor IDL receptor 34 FAMILIAL HYPERCHOLESTEROLEMIA Xanthomas (patches of yellowish cholesterol buildup) 35 LIST OF REFERENCES • Baynes, J., & Dominiczak, M. H. (2019). Medical biochemistry. Elsevier Health Sciences. Chapter 33. 489-506 • Shi Y, Burn P. (2004). Lipid metabolic enzymes: emerging drug targets for the treatment of obesity. Nat Rev Drug Discov. 3(8):695-710.