OS 201 Lipid Digestion & Lipoproteins PDF

OS 201: HUMAN CELL BIOLOGY LIPID DIGESTION & LIPOPROTEINS UPCM 2029 | Dr. Nemencio A. Nicodemus | LU3 A.Y. 2024-2025 OUTLINE A. MINOR DIGESTION...

OS 201: HUMAN CELL BIOLOGY LIPID DIGESTION & LIPOPROTEINS UPCM 2029 | Dr. Nemencio A. Nicodemus | LU3 A.Y. 2024-2025 OUTLINE A. MINOR DIGESTION Lingual and gastric lipases hydrolyze medium and long chain I. Objectives V. Lipid Absorption triglycerides II. Introduction A. Fate of Fatty Acids ○ Long chain: 13-21 carbon atoms III. Review of Lipids B. Fate of Cholesterols ○ Medium chain: 6-12 carbon atoms IV. Lipid Digestion C. Clinical Applications Attacks the sn-3 ester bond in Carbon 3, forming 1,2 A. Steps of Lipid VI. Lipoproteins diacylglycerol and free fatty acids Digestion A. Chylomicrons Important developmentally because these 2 lipases are already B. Minor Digestion B. Very Low Density active since we were born C. Major Digestion Lipoproteins (VLDLs) ○ Digests human milk; can penetrate into the milk fat globule and D. Formation of Mixed C. Low Density initiate the digestive process Micelles Lipoproteins (LDLs) ○ No lipase = malabsorption of nutrients D. High Density Lipoproteins (HDLs) B. MAJOR DIGESTION Gastric lipase begins actual lipid digestion I. OBJECTIVES ○ 10% of TAGs are mainly hydrolyzed in the stomach To describe the processes involved in the digestion of dietary lipids Entry of chyme in the stomach → stimulates duodenum to release To discuss how dietary lipids are absorbed Cholecystokinin (CCK) → triggers the release of bile from the To explain the transport of lipids and the role of lipoproteins in this gallbladder process Bile is stored in the gallbladder and synthesized in the liver ○ Responsible for emulsifying fat II. INTRODUCTION ○ Breakdown of large fat globules into smaller, uniformly As of 2021, ischemic heart disease and stroke are the leading distributed particles causes of death in the Philippines ○ Composition of bile is mostly water ○ There was an increase in cases during the pandemic ○ Also caused morbidity and disability Leading Risk Factor: High Blood Pressure ○ High LDL (Low Density Lipoprotein) III. REVIEW OF LIPIDS 3 Types of Lipids ○ Simple ○ Complex ○ Precursor and Derived Triglycerides (fats and oils) make up more than 95% of our diet ○ Predominant lipid in diet ○ Plants, animals, olive oil, corn, nut, milk, cheese Structure: Glycerol backbone + three fatty acids Figure 3. Composition of Bile. Connection with pancreas ○ Releases pancreatic juices into the duodenum via the pancreatic duct which joins with the common bile duct before entering the duodenum Figure 1. Classification of Lipids (2027 Trans) IV. LIPID DIGESTION SIX STEPS OF LIPID DIGESTION AND ABSORPTION Minor digestion of triacylglycerols in mouth and stomach by lingual lipase and gastric lipase (acid-stable enzymes) Major digestion of all lipids in the lumen of the duodenum and jejunum by pancreatic lipolytic enzymes (pancreatic lipase) Bile acid facilitated formation of mixed micelles that present the lipolytic products to the mucosal surface, followed later by enterohepatic bile acid recycling ○ Bile → Micelles → Recycle Passive absorption of the lipolytic products from the mixed micelle into the intestinal epithelial cell Figure 4. Reaction of Lipases with TAGI to form 1,2-diacylglycerol and FAs. Re-esterification of 2-monoacylglycerol, lysolecithin, and cholesterol with free fatty acids inside the intestinal enterocyte C. FORMATION OF MIXED MICELLES Assembly and export from intestinal cells to the lymphatic chylomicrons coated with Apolipoprotein B48 and containing BILE triacylglycerol, cholesterol esters, and phospholipid Alkaline solution composed of bile acids/salts, cholesterol, lecithin, bilirubin (gives bile its green color) Synthesized in the liver Stored in the gallbladder Bile salts ○ Polar derivatives of cholesterol Cholic acid Chenodeoxycholic acid Deoxycholic acid Lithocholic acid ○ Amphipathic, with detergent properties ○ Bind strongly to hydrophobic molecules Figure 2. Lipid Digestion (2027 Trans) Trans 04 TG12: Gala, Gan, Garcia F, Garcia I, Garcia J, Gelacio, Genio TH: Oribello 1 of 10  Figure 5. Bile Chemical Structure FUNCTIONS OF BILE Emulsify fat globules into smaller micelles Figure 8. Co-lipase as a Cofactor to Lipase ○ Increase surface area accessible to lipid-hydrolyzing enzymes OTHER ENZYMES INVOLVED IN LIPID DIGESTION Phospholipase A1 and A2 ○ Secreted by the pancreas into the intestine ○ Hydrolyzes the ester linkage between the fatty acid and the hydroxyl on C2 of phospholipids Cholesterol esterase ○ Hydrolyzes fatty acids from cholesterol esters into free cholesterol and fatty acids to be absorbed Milk lipase is important for neonates for the digestion of lipids in milk ○ Good energy source for babies V. LIPID ABSORPTION Fat absorption mostly occurs in the duodenum (most proximal) or jejunum (second, convoluted part) of the small intestine Figure 6. Emulsification of Fat into Smaller Micelles with bile salts on surfaces. Micelles carry monoacylglycerols (MAG) and free FA to arrive at the intestinal epithelium, specifically the brush border, diffusing into its Solubilize lipid breakdown products enterocytes Excrete cholesterol: secretion of bile salts and cholesterol into the Bile salts will not enter epithelial cells but will be absorbed in the bile by liver is the only mechanism by which cholesterol is excreted ileum (enterohepatic circulation) ○ Enterohepatic recycling → most cholesterol and bile acids are reabsorbed in the small intestine (ileum) and returned to the liver A. FATE OF FATTY ACIDS via the portal vein and may be re-secreted FA and monoglycerides can be absorbed in the enterocytes ○ Entero = intestines; hepatic = liver Figure 7. Enterohepatic Circulation. Figure 9. FA released from micelle HYDROLYSIS OF DIETARY FATS Monoacylglycerols Pancreatic lipase hydrolyzes fat esterified at C1 and C3 positions ○ Transmitting food in the stomach is rapid → lipase is unable to act Most of the 2-monoacylglycerols are used for re-acylation to form TAGs on all lipids = a lot of left-over (fatty acids attached to C3) → ○ 1-monoacylglycerols: Hydrolyzed to FA and glycerol (~6%*) pancreatic lipase completes hydrolysis in carbon 3. Fast transit of food intestines will not allow 100% of hydrolysis ○ Triglycerides formed: sn-2 monoglyceride + 2 free fatty acids → some may retain 1-monoacylglycerols 2-monoacylglycerol: FA attached to C2 of glycerol ○ 2-monoacylglycerols: Re-acylated to TAG (~72%*) by the ○ Pancreatic lipases hydrolyze the ester bonds of the triacylglycerols process of re-acylation while in the micelles ○ Glycerol: Absorbed directly into the portal circulation (~22%*) Bile salts + pancreatic lipase = breakdown triacylglycerols to and brought back to the liver digest them *Percentage uptake may vary widely but indicate the relative ○ Leads to the formation of smaller micelles with greater surface area importance of the three routes Intestinal epithelial cells are able to absorb this Fatty Acids ○ Needs help from pancreatic co-lipase FAs that are absorbed inside the enterocytes, particularly the PANCREATIC CO-LIPASE long-chain FAs, are used in the formation of TAGs inside the enterocytes Activated by trypsin Short (2-6 C) and medium-chain (8-12 C) FA Interacts with triglyceride and pancreatic lipase ○ Enter portal blood directly from enterocytes ○ Displaces bile on the surface of micelle to allow recycling ○ Oxidized in liver or elongated and used for TAG formation ○ Attaching itself to surface of micelle for anchoring of the lipase ○ Albumin-free FA complex: FA bound to albumin (water-soluble) ○ Improves activity of pancreatic lipase to arrive to blood Anchoring mechanism → lipase to micelle Long-chain (>12 C) FA 1:1 ratio (one co-lipase to one lipase) ○ Most favored for re-esterification for TAG ○ Used for formation of TAG Packaged to form chylomicrons ○ Drain into lymphatics via the lacteals and enter bloodstream via the thoracic duct Upstream from liver OS 201 Lipid Metabolism & Digestion 2 of 10  Slow entry into the blood Figure 12. Incorporation of dietary cholesterol and TAG into micelles Figure 10. Long-chan FA are re-esterified with 2-monoacylglycerols to form TAG Cholesterol Transport Through a Channel Triacylglycerol Formation Cholesterol can be absorbed by the enterocyte via the NPC1L1 Diacylglycerol acyltransferase (DGAT) facilitates re-acylation to transport through facilitated diffusion form TAGs in enterocytes ○ Cholesterol can form ester linkages with FAs inside the ○ Long-chain FAs are re-esterified with 2-monoacylglycerols to enterocyte to become cholesteryl esters form TAGs ○ Cholesterol can also freely go out of the enterocyte via the action ○ Chylomicrons of ABCG5/G8 TAGs are used for its synthesis in enterocytes Cholesterol can freely enter and go out of the enterocytes from the Also contain proteins, cholesterol, phospholipids which are intestinal lumen already found in enterocytes Exocytosed from the enterocyte into the lymphatic system and eventually arrive in the blood Figure 13. Cholesterol transported through NPC1L1 and pumped out by ABCG5/G8 Cholesterol, TAGs, and Protein form Chylomicrons Cholesteryl esters cannot go out of the enterocyte anymore Figure 11. Fates of monoacylglycerol and FA from micelles ○ Incorporated together with the formed TAGs inside the enterocyte to form chylomicrons B. FATE OF CHOLESTEROL Chylomicrons ○ First lipoprotein particle Dietary Cholesterol ○ Distinguished through the presence of apolipoproteins B48 Important source of cholesterol in our body (apoB48 protein) on the surface Only contributes a small amount since the liver also produces a lot ○ Used to transport lipids from the intestines into the circulation by of cholesterol draining into the lacteals of the lymphatic system (yellow in Figure 13a, green in Figure 13b) and via the thoracic duct into the Table 1. Cholesterol Content of Certain Foods left subclavian vein (blue) Food Portion Cholesterol (mg) Milk (non-fat) 1 cup 4 Milk (low-fat) 1 cup 10 Milk (whole) 1 cup 33 Yogurt (non-fat) 1 cup 10 Yogurt (whole) 1 cup 29 Cheddar Cheese 1 oz 30 Cottage Cheese 1 cup 10 (low-fat) Tofu ½ cup 0 Pinto beans ½ cup 0 Egg 212 Figures 14a and 14b. Lipid transport via the lymphatic system and thoracic duct Halibut 3 ½ oz 41 Salmon 3 ½ oz 63 Oysters 3 ½ oz 55 Crab 3 ½ oz Incorporation into Micelles Fat in the diet consists of cholesterol and TAG ○ Dietary cholesterol has to incorporate into micelles to enter the intestine because of its large size Accompanied by biliary cholesterol which was already present ○ Dietary glycerides are partially broken down by pancreatic lipases into FAs and monoglycerides, which are also incorporated into micellar particles Figure 15. Formation of chylomicrons from cholesterol, TAG, and proteins C. CLINICAL APPLICATIONS Using the aforementioned principles, ○ Can you treat obesity? ○ Can you lower the cholesterol levels in the blood? OS 201 Lipid Metabolism & Digestion 3 of 10  OBESITY IN FILIPINOS ○ Side effects May cause steatorrhea DOST FNRI Survey (Figure 15) Increased lipid in feces ○ Pre-pandemic: more than half of Filipino adults had normal BMI Oily feeling when defecating or flatulence ○ Post-pandemic: an increase in the number of overweight & obese Filipinos Figure 16. Nutritional status of Filipino adults using WHO BMI Classification Mortality Figure 19. Effect of Orlistat on stool and mucosal cell ○ Obesity is secondary to stroke and ischemic heart disease LOWERING BLOOD CHOLESTEROL Enterohepatic recycling ○ Reabsorption of bile salts and cholesterol ○ 50% of cholesterol is reabsorbed in the ileum Agents that interrupt the enterohepatic cycle can be used to treat high blood cholesterol ○ Soluble Fibers Natural way of lowering blood cholesterol levels E.g. oat bran fiber and fruit pectin (apples, oranges, etc.) Bind to bile acids and/or cholesterol and prevent their reabsorption Ensures that you have smaller amounts of cholesterols absorbed and reabsorbed in the small intestines ○ Ezetimibe An NPC1L1 inhibitor Vytorin (brand name) Figure 17. Mortality attributable to high BMI in the Philippines Drug that inhibits the absorption of cholesterol into the enterocytes WEIGHT LOSS Reduces the amount of cholesterol that can be transported from the enterocyte to the circulation Obesity is not just about body image Very effective drug, reduces total cholesterol by 13 mg/dL ○ Metabolic Can be used as monotherapy or alongside other drugs called Asthma statins Gallstones Is NOT associated with many side effects Infertility Only acts locally at the intestines Cancers Indicated for familial hypercholesterolemia CVD and Risk Factors ○ Genetic problems with LDL receptors, leading to high Type 2 Diabetes Prediabetes cholesterol levels Thrombosis Gout ○ Mechanical ○ Mental Depression Anxiety ○ Physical Functioning Incontinence Arthrosis Sleep Apnea Chronic Back Pain Pancreatic Lipase Inhibition Orlistat Figure 20. Nutritional status of Filipino adults using WHO BMI Classification ○ Used as an anti-obesity drug Questions ○ Pancreatic lipase inhibitor Can any of the diets or drugs reduce the plaques that are already Blocks the hydrolysis of TAGs into monoacylglycerols and free formed in the blood vessels? FAs ○ No. There is no evidence that it can reduce the plaque that is Prevents absorption of TAGs formed. Lessens the amount of calories that enter the circulation ○ Statins are drugs that are effective in reducing the plaque If you remove the gallbladder, what will happen to bile storage? ○ Cholecystectomy: removal of gallbladder When the gallbladder has a lot of (cholesterol) stones, it blocks the release of bile, causing severe pain in the right upper quadrant, also leading to jaundice ○ Liver will be the direct source of bile Relatively less bile is released Eating a fatty meal might result into malabsorption Since biliverdin is mixed with the chyme in the jejunum and ileum, why is feces not green? ○ Biliverdin is metabolized and contributes to the yellow-brown color of feces ○ Rapid food transit can still result in green-colored feces ○ Example: A patient came to the ER for severe upper-right quadrant pain with gray-colored stool. What is your diagnosis? Obstructive jaundice due to a possible common bile obstruction (surgical diagnosis) Figure 18. Inhibitory mechanism of Orlistat Are there any studies about drugs with the same mechanism as Ezetimibe but allows the exit of cholesterol through the ○ Can only prevent the hydrolysis of 30% of TAGs, which is ABCG5/G8, instead of inhibiting the entry of cholesterol through released together with stool NPC1L1? ○ Those who take orlistat may experience some weight loss ○ None yet. Meta analysis on Orlistat concluded that it results in 3 kg of weight loss in 1 year OS 201 Lipid Metabolism & Digestion 4 of 10  VI. LIPOPROTEINS Differences in: Transport vehicles of lipids ○ Size of the neutral lipid core ○ Since lipids are very big and water insoluble ○ Lipid composition in the core Water-soluble transport forms of particulate lipid-protein ○ Apolipoprotein composition complexes E.g. apoB48 protein exists only in chylomicron Secreted by the small intestine and liver into the circulating blood Composed of lipids and special proteins Table 2. Chemical Composition of Plasma Lipoprotein Classes ○ Apolipoproteins Protein Lipid Esterified Makes the lipids water soluble Lipoprotein Phospholipid TAG % % Cholesterol HDL2 40-45 55 35 12 5 HDL3 50-55 50 20-25 12 3 LDL 20-25 75-80 15-20 35-40 7-10 IDL 15-20 80-85 22 22 30 VLDL 5-10 90-95 15-20 10-15 50-65 Chylomicron 1.5-2.5 97-99 7-9 3-5 84-89 *no need to memorize but understand which composition predominates where APOPROTEINS IN LIPOPROTEINS Figure 21. General structure of lipoproteins. Apoprotein Composition Spherical shaped Table 3. APOPROTEIN COMPOSITION OF THE LIPOPROTEINS ○ Non polar, water insoluble molecules are protected inside E.g. lipid components CHYLOMICRON VLDL IDL LDL HDL ○ Polar molecules are located outside E.g. phospholipids and proteins A-I, A-II A-I, A-II B-100 B-100 C-I, C-II, C-III B-48 C-I, C-II, C-III C-I, C-II, C-III B-100 MAJOR LIPID CLASSES PRESENT IN LIPOPROTEINS D C-I, C-II, C-III E E E 1. Triacylglycerols 2. Phospholipids Some apoproteins are unique to one lipoprotein while others are Lysophospholipid + fatty acid → phospholipid present in almost all 3. Cholesterol ○ E.g. B-48 only in chylomicron while C-I, C-II, C-III is present in all 4. Cholesteryl esters except LDL and B-100 is present in all except chylomicron and Cholesterol + fatty acid → cholesterol ester HDL 5. Free fatty acids Those that are present in almost all lipoproteins have common functions DIFFERENCES IN SIZE AND DENSITY ○ C-II is a major activator of lipoprotein lipase ○ C-III is an inhibitor of lipoprotein lipase Roles of Apoproteins 1. Structural components of lipoproteins 2. Cofactors for enzymes C-II for lipoprotein lipase A-I for lecithin-cholesterol acyltransferase (LCAT) 3. Enzyme Inhibitors A-II and C-II for lipoprotein lipase C-I for cholesteryl ester transfer protein (CETP) 4. Ligands for interaction with lipoprotein receptors in tissues Important in recognition mechanism ○ For lipoproteins to be recognized by organs that metabolize them B-100 and E for LDL receptor Figure 22. Difference in size and density of lipoproteins. A-I for HDL receptor Largest → Chylomicron TYPES OF LIPOPROTEINS Smallest → HDL 1. Chylomicrons Most Dense → HDL Chylomicron remnants Large lipoprotein particles with a high volume/surface ratio have a 2. Very Low Density Lipoproteins (VLDL) high content of nonpolar lipids Intermediate Density Lipoprotein (IDL) Small lipoproteins contain more proteins 3. Low Density Lipoproteins (LDL) 4. High Density Lipoproteins (HDL) A. CHYLOMICRONS GENERAL DESCRIPTION Converted to chylomicron remnants after a cycle of metabolism → 10% of chylomicrons are converted to chylomicron remnants → 90% of chylomicrons is broken down by lipoprotein lipase Biggest group of lipoproteins Contain the most lipids and triacylglycerols Only lipoprotein with B-48 and has no B-100 Secreted in intestine (enterocyte) Purpose: mobilize dietary lipids from intestine to body Figure 23. Difference in density of lipoproteins → TG to adipose tissue and muscle → Delivery dietary cholesterol to liver CHYLOMICRON SYNTHESIS 1. Bile salts emulsify dietary fats in the small intestine, forming mixed micelles 2. Intestinal lipases degrade triacylglycerols 3. Fatty acids and other breakdown products are taken up by the intestinal mucosa and converted into triacylglycerols 4. Triacylglycerols are incorporates with cholesterol and apolipoproteins into chylomicrons 5. Chylomicrons move through the lymphatic system and bloodstream to tissues 6. Lipoprotein lipase, activated by apoC-II in the capillary converts Figure 24. Oil-drop or Mixed Micelle Model of Lipoprotein Structure triacylglycerols to fatty acids and glycerol OS 201 Lipid Metabolism & Digestion 5 of 10 7. Fatty acids enter cells ○ Similar process to growth of nascent chylomicrons 8. Fatty acids are oxidized as fuel or reesterified for storage Core structural protein of VLDLs is apoB-100 ○ Each VLDL particle contains 1 apoB-100 ○ No apoB-48 present, in contrast to chylomicrons Size can vary depending on quantity of TGs ○ If TG production in liver is high, VLDLs are large ○ However, they are still smaller than chylomicrons VLDL SYNTHESIS Figure 25. Overview of Chylomicron Synthesis. FUNCTIONS OF CHYLOMICRONS Figure 28. Synthesis of triglycerides within the liver. Fat and excess carbohydrates from dietary intake are converted to TGs in the liver Hepatic TG synthesis provides immediate stimulus for VLDL formation & secretion ○ Fatty acids (FAs) utilized in TG synthesis may come from: FA synthesis within the liver from acetyl-CoA (well-fed state) Figure 26. Chylomicron functions. Uptake of free FAs from circulation (starved state) Deliver TG to the adipose tissue and muscle VLDL synthesis in the liver involves transfer of TGs and cholesteryl esters to newly-synthesized apoB-100 within the Deliver dietary cholesterol to the liver endoplasmic reticulum Source of energy ○ Triglyceride transfer is mediated by microsomal triglyceride ○ In the form of the triacylglycerol transfer protein (MTP) Triacylglycerol is broken down by lipoprotein lipase MTP is required for early addition of lipids to apoB-100 C-II and C-III regulates this enzyme However, additional lipids are added via pathways that do not ○ These proteins are exchangeable proteins require MTP Can be exchanged between HDL and triglyceride rich ○ Cholesteryl esters are transferred from HDLs to VLDLs via particles in chylomicron cholesteryl ester transfer protein (CETP) A-I, A-II, A-IV, C-I, C-II, C-III, E Simultaneously, TGs are transferred from VLDLs to HDLs in an exchange reaction LIPOPROTEIN LIPASE ○ Availability of TGs is primary determinant of the rate of VLDL Located on the walls of the blood capillaries in endothelium and synthesis anchored by heparan sulfate NOT the rate of synthesis of apoB-100 Found in heart, adipose tissue, renal medulla If TG supply is limited, newly synthesized apoB-100 is rapidly ○ Main fuel of the heart degraded → amount of available lipid determines if apoB-100 is ○ Reason why there is a lot of glycoprotein lipase in capillaries of degraded or secreted heart to be able to extract energy from triacylglycerol Loss-of-function mutations in either apoB-100 or VLDL: Activated by C-I and C-II; inhibited by C-III ○ Results in failure to produce VLDL Hydrolysis occurs when the lipoproteins attach to it ○ Marks decrease in plasma triglyceride & cholesterol levels ○ Removes FA of TG in the chylomicrons ○ Related conditions include familial hypobetalipoproteinemia & abetalipoproteinemia CHYLOMICRON METABOLISM 80% of fatty acids originating from chylomicron TG are delivered VLDL METABOLISM mainly to adipose tissue, heart, and muscle while 20% goes to liver It becomes chylomicron remnant after acted upon by LPL ○ Can go back to liver for metabolism ○ 90% loss of TG and apo C Hepatic lipases hydrolyze the TG and phospholipids in the Chylomicron remnant B. VERY LOW DENSITY LIPOPROTEINS (VLDLs) VLDL STRUCTURE Figure 29. Metabolism of VLDLs. Almost the same process as chylomicron pathway, but VLDLs start from the liver ○ VLDL will circulate, encounter the lipoprotein lipase that extracts the FAs, becomes a smaller remnant in the form of an IDL that can either go back to the liver to be metabolized or be Figure 27. Structure of VLDLs. converted into an LDL Enzymes in the liver (to be discussed further in the Transport vehicles of triglycerides (TGs) from the liver to succeeding parts) act upon the IDL to turn it into IDL extrahepatic tissues (e.g. muscle, adipose tissue) for ○ Without IDL from VLDL, there is no LDL storage/energy ○ Also carry cholesterol from the liver, but is primarily rich in TGs VLDL METABOLISM [2028 Trans] When metabolized, produces IDLs (VLDL remnants) VLDL particles are transported from the liver to peripheral Newly released VLDLs acquire the lipoproteins apoC and apoE tissues where the TGAs are hydrolyzed by LPL and fatty from circulating HDLs acids are released ○ They start out flat before acquiring these lipoproteins OS 201 Lipid Metabolism & Digestion 6 of 10  ○ There is competition between the metabolism of chylomicrons and VLDL ○ High levels of chylomicrons inhibit VLDL clearance Removal of triglycerides from VLDL results in the formation of VLDL remnants → IDL ○ two fates of IDL: Taken up by the liver via the LDL receptor (requires APO B-100, E) Converted to LDL Intermediate density lipoproteins (IDL): relatively enriched in cholesterol esters and acquire Apo E from HDL particles IDL particles are removed from the circulation by the liver via binding of ApoE to LDL and LRP receptors, ○ While majority of chylomicron remnants are rapidly cleared by the liver, only a fraction of IDL particles are cleared (~50%) ○ The remaining triglycerides in IDL particles are hydrolyzed ○ by hepatic lipase Lead to further decrease in triglyceride content Exchangeable apolipoproteins are transferred Figure 32. Uptake of LDLs by the liver and extrahepatic tissues from the IDL particles to other lipoproteins Lead to the formation of LDL which THE FATE OF LDLs predominantly contain cholesterol esters and Apo B-100 LDL delivers cholesterol to extrahepatic tissues like the adrenal glands and gonads ○ Cholesterol serves as a precursor to steroid hormones such as aldosterone, cortisol, testosterone, and estradiol C. LOW DENSITY LIPOPROTEINS (LDLs) LDL STRUCTURE Figure 30. Structure of LDLs Figure 33. The fate of cholesterol delivered by LDLs Outer membrane contains a phospholipid monolayer, unesterified REMOVAL OF LDLs IN THE PLASMA cholesterol, and apo-B protein Inner core contains triglycerides and highly lipophilic cholesterol LDL can be effectively cleared from circulation through endocytosis esters LDLs is removed in the plasma in two ways: apo-B-100 → major apoprotein in LDL ○ Via uptake by the liver (75%) Role of LDL: LDLs serve as primary carriers of cholesterol in the Receptor-mediated (75%) blood for delivery to peripheral tissues [2028 Trans] Receptor-independent (25%) ○ Via uptake by hepatic tissues (25%) LDL FORMATION IN PLASMA Receptor-mediated (66%) The conversion of VLDLs to LDLs is a two-step process involving Receptor-independent (34%) the action of lipoprotein lipase and hepatic lipase LDL removal via receptor-mediated endocytosis requires the ○ Without VLDL (IDL), you cannot create LDL presence of apo-B-100 (major apoprotein of LDL) [2028 Trans] ○ LDLs are the end-products of VLDL metabolism Once formed, LDLs are brought to circulation via the uptake of LDL REMOVAL PATHWAY VIA RECEPTOR-MEDIATED extrahepatic tissues and the liver ENDOCYTOSIS [2028 Trans] 1. LDL is taken up via receptor-mediated endocytosis Involve the formation of clathrin-coated pits (LDL receptor binds to apoB100) 2. Endocytosed vesicles fuse with lysosomes 3. Apoproteins get degraded and cholesterol esters become hydrolyzed to yield free cholesterol 4. Cholesterol is incorporated into the plasma membrane, while excess is re-esterified by acyl-CoA cholesterol-acyltransferase (ACAT) 5. LDL receptors get recycled back to the cell membrane Figure 31. Formation of LDLs in plasma OS 201 Lipid Metabolism & Digestion 7 of 10  Outer membrane contains a phospholipid monolayer, unesterified cholesterol, and apoproteins Inner core is composed of esterified cholesterol and triglyceride Contains a special protein called apoprotein A-1 ○ Serves as a co-factor for lecithin-cholesterol acyl transferase (LCAT) apo-C and apo-E - synthesized in the liver THE ROLE OF HDLs HDL primarily functions as a repository for the apo-C and apo-E required for the metabolism of chylomicrons and VLDL HDL is also known as the “good cholesterol” [2028 Trans] ○ Scavenger for cholesterol from peripheral tissues Excess cholesterol is either taken up by the liver (via reverse cholesterol transport) or used for steroid hormone formation (e.g. estrogen and testosterone) Figure 34. Pathway for receptor-mediated endocytosis of LDLs CLINICAL CORRELATES Fatty acids serve as the main fuel of the resting heart ○ However, too much of it can lead to serious health consequences Atherosclerosis - consequence of excess LDL in the blood Sequence of events: ○ Endothelial dysfunction → inflammation → oxidation → plaque Figure 38. Scavenging of cholesterol from peripheral tissues by HDL [2028 Trans] instability and thrombosis HDL SYNTHESIS AND METABOLISM When a thrombus blocks coronary arteries, it may result in Unlike other lipoproteins, HDLs are synthesized by both myocardial infarction enterocytes and hepatocytes (unique feature) Ischemic heart disease and stroke are both due to atherosclerosis ○ These cells secrete lipid-poor apoA-I [2028 Trans] ○ If unstable plaque ruptures, it may cause a heart attack ○ ApoA-I acquires free cholesterol and phospholipids from these ○ If blood clot blocks blood flow to the brain, a stroke may occur cells via the ABCA1 pathway and converts them to nascent (immature) HDL [2028 Trans] Figure 35. Atherosclerosis caused by excess LDL in the blood Figure 39. Secretion, lipid acquisition, and maturation of HDL particles What does HDL do with cholesterol? Returned to the liver for cholesterol metabolism Cholesterol esters can be transferred to VLDL and LDL via the action of cholesterol ester transfer protein (CETP) ○ CETP is also known as apo-D These two processes allow the excess cholesterol to be returned to the liver through the LDL-receptor pathway and the HDL-receptor pathway REVERSE CHOLESTEROL TRANSPORT Figure 36. Possible complications of atherosclerosis Reverse cholesterol transport involves the removal of excess cholesterol from other cells, returning them to the liver D. HIGH DENSITY LIPOPROTEINS (HDLs) Involves the action of lecithin-cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) HDL STRUCTURE Esterification of the collected cholesterol by LCAT → less soluble cholesterol esters → migration to the core of HDL Cholesterol esters can be transferred to VLDL or LDL with the facilitation of CETP/apo-D → cholesterol uptake via endocytosis Figure 37. Structure of HDLs OS 201 Lipid Metabolism & Digestion 8 of 10  Figure 40. Reverse cholesterol transport Figure 41. Summary of lipoprotein synthesis CLINICAL CORRELATES Lipoprotein profile test ○ Test that measures levels of different lipids in the blood, mainly total cholesterol (TC), LDL, HDL, and triglycerides (TG) 1 ○ Formula: 𝐿𝐷𝐿 𝑐ℎ𝑜𝑙 = 𝑡𝑜𝑡𝑎𝑙 𝑐ℎ𝑜𝑙 − (𝐻𝐷𝐿 𝑐ℎ𝑜𝑙 + 4 𝑇𝑔) Figure 41. Lipoprotein profile test VII. REFERENCES Nicodemus, N.A. (2024). Lipid Digestion and Lipoproteins [Powerpoint Presentation] UPCM 2028 Trans. Lipid Digestion and Lipoproteins OS 201 Lipid Metabolism & Digestion 9 of 10  APPENDIX Figure 2. Lipid Digestion (2027 Trans) OS 201 Lipid Metabolism & Digestion 10 of 10