Advanced Nutrition Lipids 5 MargiAnne Isaia, MD MPH

LIPIDS LIPOPROTEIN ASSEMBLY AND METABOLISM Lipoproteins - complex lipids=lipids bound to other molecules core: hydrophobic lipids (TG,CE) surface: hydrophilic lipids (UC,PL) TG = triglyceride, CE = cholesterol ester UC= un-esterified cholesterol, free C; PL= phospho-lipids Protein – more hydrophilic – on the surface Lipids - transported: by albumin (FAs – albumin) by complex with protein, as LP (lipoproteins) as TG, CE, PL

LIPIDS LIPOPROTEIN – GENERAL STRUCTURE

LIPIDS LIPIDS Triacylglycerol = Glycerol backbone + 3FFA -the main constituent of dietary fats, -used for energy storage in adipose tissue Phospholipids = Glycerol backbone + 2FFA (usually saturated) + 1 highly unsaturated FFA + bipolar head group – Phosphoric Acid and Choline used as structural component in cell membranes donate FFA to form Eicosanoids Cholesterol, Cholesterol Esters - membrane component precursor of bile acids, vit D, steroid hormones Lipoproteins – Chylomicron CM VLDL- C, LDL- C, HDL- C

LIPIDS APOLIPOPROTEINS In the structure of lipoprotein (in the shell of LP) Apo A-I ( liver, small intestine) - structural, activator of Lecithin Cholesterol Acyltransferase LCAT Apo B-100 (liver) - structural, synthesis of VLDL-C, ligand for LDL –receptor Apo B-48 (small intestine) - structural, synthesis of chylomicrons, derived from apo B-100 mRNA following specific mRNA editing - ligand for CM uptake Apo C-II (liver) - activator of LPL (lipoprotein lipase) Apo E (liver, macrophages, brain) - ligand for Apo E-receptor; moblization of cellular cholesterol

APOLIPOPROTEINS

LIPIDS LIPOPROTEIN CLASSES size density Chylomicrons, VLDL-C and their remnants >30 nm D < 1.006 g/ml LDL-C 20- 22 nm D = 1.015 -1.063 g/ml HDL-C 9-15 nm D = 1.063 – 1.21 g/ml

LIPOPROTEIN METABOLISM LIPIDS LIPOPROTEIN METABOLISM Dietary fats g exogenous pathway – chylomicrons pathway TG g CM g TG Lipids synthesized by the liver g endogenous pathway HDL-C metabolism HDL-C functions – donor (Apolipoprotein transfer) - Cholesterol-ester transfer - reverse Cholesterol transfer (brings Cholesterol again to the liver) Cholesterol – bile acids synthesis in the liver g intestine g stools 98% of Cholesterol saved (bile salts re-absorption) If BS elimination increases, BS re-absorption decreases g Cholesterol pool diminishes – up-regulation of LDL–R g up-take of Cholesterol from blood increases g blood level of Cholesterol decreases

LIPIDS TG RICH: CHYLOMICRONS CM: Hydrophobic core: TG(93%), CE (1%) Surface monolayer: PL(5%), free Cholesterol (1%), protein (1%) Proteins: Apo B-48, main Apolipoprotein, structural, required to package Apo A-I, structural, activation of LCAT Apo C-II, activator of LPL Apo E, ligand for Apo E receptor

LIPIDS CM METABOLISM LCFA are re-esterified into TG in the gut and transferred CM are synthesized and secreted into the blood via lymphatic circulation Apo B-48 is attached and required for release of CM from the epithelial cells into the lymphatic vessels . In the blood CM acquires Apo C-II and Apo E from HDL-C In capillaries of adipose tissue (and muscle) Apo C-II activates LPL* LPL = endothelial cell membrane bound enzyme FFAs are released from TG (CM ) and enter the tissue, Glycerol enters the liver (contains Glycerol kinase) CM lowers TG percentage, becomes CM remnants – and is released to hepatocytes (Apo E receptor) LPL* = Lipoprotein Lipase

LIPIDS TG Rich: VLDL-C Core: hydrophobic TG (65%); CE 8% Surface: PL(12%); UC (14%); Protein (4%) Protein: Apo B-100, main protein Apo C-II, activator of LPL Apo E, ligand for Apo E receptor - uptake of remnants by the liver. VLDL-C – assembled in hepatocytes - to transport TG containing FFA newly synthesized - from excess glucose (endogenous lipids) - from CM remnants Apo B-100 is added in hepatocytes, to be released into the blood Apo C-II and Apo E from HDL-C are received in the blood From TG, FFA are delivered (LPL action on VLDL-C) to adipose tissue and muscle VLDL-C remnants (IDL-C)g taken by the liver

LIPIDS VLDL- C METABOLISM VLDL-C delivers FFA (LPL action) and results in VLDL-C remnant (IDL-C) VLDL-C remnant 60-70% taken by the liver, if it contains Apo E 39-40% becomes LDL-C (CE from HDL -C are added under the action of Cholesterol Ester Transfer Protein, CETP, into the blood) Free Fatty Acid transport Apo C-II activates LPL which catalyses the hydrolysis of TG -FFA released, complexed with albumin g FFA–albumim (it is delivered to: muscle g energy adipose-tissue g TG storage liver g TG synthesis)

LIPIDS CE Rich: LDL-C Low Density Lipoprotein hydrophobic core: TG 5%, CE 35% surface: PL 25%, UC 15%, protein 22% (Apo B-100 main Apolipoprotein) LDL-C is removed by Apo B-100 receptors (which are mainly expressed in the liver) endocytosis by the liver – via Apo B-100 R (receptor) (75%) endocytosis by peripheral tissues – via Apo B-100 R (25%) Uptake by the liver: R- mediated 3/4 & Non - R mediated 1/4 Uptake by extra-hepatic tissues: R mediated 2/3 & Non - R mediated 1/3 Defects in LDL-C receptors result in Familial Hypercholesterolmia

LIPIDS LIPOPROTEINS METABOLISM

LIPIDS CE Rich : HDL-C High Density Lipoprotein - Hydrophobic core: TG 5%, CE 18% - Surface: PL 25%, UC 7%, Protein 45% Apo A-I, activator of LCAT, main protein Apo E, ligand for Apo E receptor, mobilization for cellular cholesterol Apo C, activator of LPL HDL –C is secreted in a discoid form by the liver and gut (many subpopulation) As it acquires Cholesterol from tissues in the circulation, it matures into a spherical form through the action of Lecithin Cholesterol Acyl-Transferase ( LCAT) LCAT adds a FFA to Cholesterol producing CE, which dissolve in the core of HDL-C, allowing HDL-C to transport Cholesterol from periphery to the liver (process of reverse Cholesterol transport)

LIPIDS HDL-C CONVERSION HDL-C cycle : HDL-C 3 g HDL-C 2a g HDL-C 2b g HDL-C 3 HDL-C carries Apo E and Apo C-II for donating them temporarily to CM and VLDL-C CE can be distributed to other lipoprotein particles (IDL-C) (enzyme CETP) Genetic defect: deficiency of Cholesterol Ester Transfer Protein (CETP) results in accumulation of HDL-C 2a, which gets oxidized

LIPIDS HEPATIC CHOLESTEROL METABOLISM (Intracellular Cholesterol regulation) Dietary and biliary Cholesterol “De novo” synthesis (in the liver) Cholesterol from extra-hepatic tissues absorption reverse transport Liver Cholesterol pool catabolism transport synthesis Endogenous lipoprotein pathway (VLDL-C) Biliary excretion: bile acids and Cholesterol Steroid hormones

LIPIDS

LDL-C CELULAR METABOLISM LIPIDS LDL-C CELULAR METABOLISM LDL-C taken up by the LDL-C receptors (R) g endosome LDL-C R made in Golgi complex LDL-C & LDL-C R complex splits and LDL-C R is recycled LDL-C particle taken in lysosome delivers Acetyl-CoA and Cholesterol Esters to the cytoplasm Increases of Cholesterol pool down regulate LDL-C R represse HMG – CoA reductase It stops producing endogenous CH Increased activity of ACAT (Acyl-CoA Cholesterol Acyl-Transferase) increases CE formation and decreases Cholesterol pool It results in up-regulation of LDL–C R and h uptake of LDL-C by the liver Consequently, blood LDL-C decreases

CELLUAR FREE CHOLESTEROL – protein gene expression LIPIDS CELLUAR FREE CHOLESTEROL – protein gene expression Sterol Regulatory Element Binding Protein (SREBP) a protein required to bind Promoter region of the gene (the gene g activated, transcriptional activation) Genes: HMG –CoA reductase gene LDL-C R gene SREBP is trapped in ER as precursor because protease is inhibited in cases of normal/high cellular free Cholesterol SREBP inactive - genes are repressed - no cholesterol synthesis (regulation of HMG-CoA reductase by repression) SREBP is active- because protease is active in cases of low cellular C, SREBP binds to Promoter region of the gene – it follows transcriptional activation: induction of HMG-CoA reductase and LDL-C receptors - stimulates cholesterol synthesis (regulation of HMG-CoA reductase by induction)

LIPIDS REFERENCES 1. Shils M et al, Modern Nutrition in Health and Disease, 10th Edition 2. www. Pubmed.org

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