Lipid Metabolism Prof. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel

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Lipid Metabolism Department of Biochemistry and

Lipids. visceral fat. nutritional lipids 0 1.5 3 4.

lipid accumulation in the arterial wall Karpe et al.

lipids nergy supply Phospho- and shingolipids as

1 Lipid Metabolism Department of Biochemistry and Molecular Biology II Medical Center Hamburg-ppendorf 1 Lipids. visceral fat. nutritional lipids h. serum lipids. lipid accumulation in the arterial wall Karpe et al., Atherosclerosis Triglycerides Functions of lipids nergy supply Phospho- and shingolipids as structural membrane components Fatty acids Cholesterol Hormones Regulation of gene expression Lipophilic vitamins 3 1

2 Lipid metabolism 1. Postprandial lipid metabolism 2. Hepatic lipid metabolism 3. Cellular cholesterol homoeostasis 4. Reverse cholesterol transport 4 Lipid absorption in the intestine nutritional lipids in: Lipid droplets nterocytes + phospholipids + bile acids + pancreatic lipase with cofactor Lipid emulsion Micelles cholesterol fatty acids bile acids entero-hepatic cycle 5 Intestinal sterol uptake nterocytes cholesterol and plant sterols plant sterols and cholesterol NPC1L1 ABCG5/G8 Niemann-Pick C1 Like 1 (NPC1L1) protein is responsible for sterol absorption in the small intestine 1 and The secretion of sterols into bile is mediated jointly by the two ABC-transporters ABCG5 and ABCG8 2 1) Altmann SW et al., Science ) Berge K et al., Science

Intestinal fatty acid uptake nterocytes Fatty acids and cholesterol CD36 proximal CD36 is a fatty acid translocase (FAT) with a broad ligand specificity Fatty acids FATP4 distal Fatty acid transport

3 Intestinal fatty acid uptake nterocytes Fatty acids and cholesterol CD36 proximal CD36 is a fatty acid translocase (FAT) with a broad ligand specificity Fatty acids FATP4 distal Fatty acid transport protein 4 (FATP4) is a member of the large family of fatty acid transport proteins Stahl A et al., Mol Cell 1999; Nassir F et al., JBC Intestinal chylomicron formation short chain FA nterocyte albumin-bound to liver long chain FA cholesterol lipophilic vitamins microsomal triglyceride transport protein (MTP) Chylomicron formation via lymph into the blood stream DAG and MAG Apo B48 Chylomicrons = intestinal triglyceride-rich lipoproteins Hussain et al., JLR Postprandial hyperlipidemia Blood samples from a healthy young maleafter a heavy meal (1950 kcal) Most of the day we are in the postprandial state! hours Heeren and Beisiegel Karpe et al., Atherosclerosis

Lipoprotein model cholesterol esters triglycerides amphipatic ß sheet phospholipids free cholesterol

publishing house 10 Major lipoproteins and apoproteins B-48 Intestinal derived chylomicrons - mainly apo

density lipoproteins (HDL) apo AI HDL 3 HDL 2.

4 Lipoprotein model cholesterol esters triglycerides amphipatic ß sheet phospholipids free cholesterol amphipatic helices Löffler/Petrides/Heinen, Textbook on `Biochemie & Pathobiochemie ; Springer publishing house 10 Major lipoproteins and apoproteins B-48 Intestinal derived chylomicrons - mainly apo B48. hydrolyzed in blood to chylomicron remnants B- 100 Liver derived very low density lipoproteins p (VLDL) - VLDL Apo B100 and apo 3 LDL. hydrolyzed in blood to low density lipoproteins (LDL) HDL-precursor Intestinal derived precursor of high density lipoproteins (HDL) apo AI HDL 3 HDL 2. matures in blood to HDL 3 and HDL 2 11 Apo B100 and Apo B48 are derived from one gene Apo B100 mrna is edited by APOBC1 to yield apo B48 Apo B100 receptor binding site NH 3 Apo B48 NH 3 no receptor binding Davidson et al., Annu Rev Nutr

Postprandial lipoprotein metabolism oral fat intake B-48 HDL Lipoprotein Lipase

, J Mol Med 2002 13 Insulin as major postprandial hormone oral fat intake Insulin

, JCI 1982 14 Metabolism of adipose tissue Anabolic: Insulin effects Uptake of fatty

5 Postprandial lipoprotein metabolism oral fat intake B-48 HDL Lipoprotein Lipase Beisiegel et al., PNAS 1991 Heeren J et al., J Mol Med Insulin as major postprandial hormone oral fat intake Insulin muscle + fatty acids adipose tissue Lipoprotein Lipase Sadur et al., JCI Metabolism of adipose tissue Anabolic: Insulin effects Uptake of fatty acids FATP1 Leptin TNFα and IL-6 Catabolic: Glucagon and adrenalin effects HSL Free fatty acid release Trujillo M and Scherer P, ndocrine Reviews

6 Nutritional lipids are also delivered to the bone Hussain MM et a., JBC 1989 Niemeier et al., J Bone Miner Res 2005 oral fat intake Intestinal synthesis of chylomicrons hepatic clearance Lipoprotein Lipase Fatty acids Muscle Adipose tissue 16 oral fat intake Chylomicron remnants deliver Lipids and vitamin K to the bone The vitamin K-dependent carboxylation of osteocalcin is necessary for bone formation Vit K LRP1 Vit K Vit K Niemeier et al., Bone Lipid metabolism 1. Postprandial lipid metabolism 2. Hepatic lipid metabolism 3. Cellular cholesterol homoeostasis 4. Reverse cholesterol transport 18 6

7 Hepatic lipid metabolism: what are the receptors responsible for uptake?? Beisiegel et al., Nature 1989 Rohlmann et al., JCI Hepatic receptors for lipoprotein uptake I NH 2 LRP1 LDLR class A repeat α-subunit II III GF like modules β-propeller O-linked sugar domain LDL Receptor LDL Receptor-Related Protein 1 LDLR β-subunit NH 2 IV NPXY NPXY NPXY Heeren and Beisiegel 2008 ligand binding domain GF precursor homology domain O-linked sugar domain Transmembrane domain cytosolic domain Beisiegel et al., Nature 1989 Rohlmann et al., JCI 1998 Lillis et al., Physiol Rev uptake into the liver LRP1 LRP1 Insulin LDLR Laatsch et al., Atherosclerosis

Hepatic lipoprotein pathways B-100 VLDL 3 B-48 LRP1 Lipoprotein Lipase LDLR B-100 IDL 3 Lipases B-100 LDL LDLR Peripheral Tissue 3 B-48 22

CIII Apo CII Apo LPL IDL LPL HL Small dense LDL Apo B 100 FFA Apo B 100 Berneis et al.

8 Hepatic lipoprotein pathways B-100 VLDL 3 B-48 LRP1 Lipoprotein Lipase LDLR B-100 IDL 3 Lipases B-100 LDL LDLR Peripheral Tissue 3 B Size of VLDL determines LDL size Normal hepatic VLDL Apo CIII Apo CII Apo LPL IDL LPL HL Normal LDL Apo B 100 FFA Apo B 100 Large VLDL Apo CIII Apo CII Apo LPL IDL LPL HL Small dense LDL Apo B 100 FFA Apo B 100 Berneis et al., JLR 2002 Packard CJ, Curr Opinion Lipidol Role of apo in lipoprotein catabolism B-100 VLDL B-48 3 LRP1 Lipoprotein Lipase B-100 IDL 3 LDLR B-100 LDL Schaefer et al., JCI B

9 Apo polymorphism Apo3 (frequency 0.77) H 2N Cys 112 Arg 158 Receptor Binding Domain Apo2 (frequency enc 0.08) 08) H 2N Apo4 (frequency 0.15) Cys 112 Cys 158 reduced binding to LDL-Receptor associated with Typ-III HLP H 2N Arg 112 Arg 158 associated with hyperlipidemia and coronary heart disease Utermann et al., Hum Genet 1982 Bennet et al., JAMA Lipid metabolism 1. Postprandial lipid metabolism 2. Hepatic lipid metabolism 3. Cellular cholesterol homoeostasis 4. Reverse cholesterol transport 26 LDL receptor involved in cellular cholesterol homeostasis LDLR NH 2 ligand binding domain GF precursor homology domain Nobel Prize 1985 to J.L. Goldstein and M.S. Brown Brown and Goldstein, Science 1986 O-linked sugar domain Transmembrane domain NPXY cytosolic domain Heeren and Beisiegel

10 Intracellular cholesterol regulated gene expression LDL Receptor 3. LDL-Receptor Synthesis 2. Cholesterol Synthesis HMG-CoA Reductase LDL Cholesterin ACAT 1. Cholesterol- Storage Cholesterol acts via the SRBP* Free intracellular cholesterol regulates synthesis, storage and uptake of cholesterol via regulating the expression of the genes for HMG CoA reductase, ACAT and LDL-receptor ACAT= Acyl-Cholesterin-Acyl-Transferase SRBP = Sterol regulated element binding protein Goldstein and Brown, Science 1986 *Brown and Goldstein, PNAS 1999 *Gong Y et al., PNAS Lipid metabolism 1. Postprandial lipid metabolism 2. Hepatic lipid metabolism 3. Cellular cholesterol homoeostasis 4. Reverse cholesterol transport 29 Reverse cholesterol transport by HDL SR-B1 Apo AI Periphery Apo AI HDL-precursor HDL 2 Cholesterol ABCA1 Apo AI HDL 3 Von ckardstein A et al., ATVB

Lipid exchange proteins SR-B1 C HDL 2 LCAT Periphery HDL-precursor Cholesterol Phospholipids PLTP Triglycerides HDL 3 VLDL or Chylomicrons CTP Cholesterol

, ATVB 2000 31 Normal levels for plasmalipids In mg/dl; generalized from several international recommendations Fasting Postprandial Total cholesterol < 200 <

11 Lipid exchange proteins SR-B1 C HDL 2 LCAT Periphery HDL-precursor Cholesterol Phospholipids PLTP Triglycerides HDL 3 VLDL or Chylomicrons CTP Cholesterol PLTP = phospholipid transfer protein CTP= cholesterol ester transfer protein Von ckardstein A et al., ATVB Normal levels for plasmalipids In mg/dl; generalized from several international recommendations Fasting Postprandial Total cholesterol < 200 < 200 LDL- cholesterol < 130 < 130 HDL- cholesterol > 40 > 40 Total triglycerides < 150 < relates to primary prevention and is not differentiated for gender 32 Dietary lipids Nordestgaard et al., JAMA

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Lipids digestion and absorption, Biochemistry II

Lipids digestion and absorption, blood plasma lipids, lipoproteins Biochemistry II Lecture 1 2008 (J.S.) Triacylglycerols (as well as free fatty acids and both free and esterified cholesterol) are very