1. Advanced Nutrition
Lipids 5
MargiAnne Isaia, MD MPH

2. 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

3. LIPIDS
LIPOPROTEIN –
GENERAL STRUCTURE

4. 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

5. 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

6. APOLIPOPROTEINS

7. LIPIDS
LIPOPROTEIN CLASSES size density
Chylomicrons,
VLDL-C and their remnants >30 nm D < g/ml
LDL-C nm D = g/ml
HDL-C nm D = – 1.21 g/ml

8. 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

9. 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

10. 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

11. 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

12. 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)

13. 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

14. LIPIDS
LIPOPROTEINS METABOLISM

15. 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)

16. 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

17. 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

18. LIPIDS

19. 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

20. 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)

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

22. QUESTIONS?
QUESTIONS?
QUESTIONS?
QUESTIONS?
QUESTIONS?
QUESTIONS?
QUESTIONS?
QUESTIONS?
QUESTIONS?
QUESTIONS?
QUESTIONS?