LIVER Glucose can can NOT be made from fatty acids Glucose Ketone bodies Glucose Fatty acids Glycerol VLDL Glucose can can NOT be made from fatty acids TCA cycle FED FASTING

Roles of Various Tissues in TG metabolism: MUSCLE Glucose Fatty acids Ketone bodies Glucose Acetyl-CoA Lactate (anaerobic) TCA cycle (aerobic) Not possible FED FASTING

Hormone sensitive lipase Insulin  mobilization Control by Hormone sensitive lipase Insulin  mobilization VLDL Chylomicrons (liver) (intestine) L.P.Lipase Albumin Fatty acids Fatty acids Triacylglycerol Glucose Glycerol Control by GLUT-4 & L.P.Lipase Insulin  uptake FED FASTING

PPAR  Increased PPAR activity increases the amount of many adipocyte proteins as well as proteins in other tissues. Thiazolidinediones (TZDs) increase the sensitivity of tissues to the effects of insulin;Type II diabetics have decreased insulin sensitivity. TZDs work by increasing the activity of PPAR The exact reason for the increased insulin sensitivity is not clear.

INTESTINE Food & Bile salts Bile salts Fatty acids 2-Monoacylglycerol Pancreatic Lipase Fatty acids 2-Monoacylglycerol Other lipids Acly-CoA Triacylglycerol Apolipoprotein B-48 Chylomicrons Lymph

Chylomicron formation The process is analagous to VLDL formation in the liver BUT Apolipoprotien B-48 is used rather than Apolipoprotien B-100 Lipids are packaged as apolipoprotein B-48 is being synthesized: chylomicron From Shelness & Sellers (2001) Curr Opin Lipidology 12:151-157

Chylomicron formation The same gene gives rise to both Apolipoprotien B-48 and Apolipoprotien B-100. The mRNA for apoliprotein B-48 is derived from the apolipoprotein B-100 mRNA by tissue specific mRNA editing. In intestinal cells an enzyme deaminates a specific cytidine nucleotide to Uridine. This highly specific C to U change introduces a stop codon, resulting in a shorter protein: apolipoprotein B-48 CAA B100 (made in liver) mRNA editing Stop codon UAA B48 (made in intestine)

BRAIN Fatty acids Glucose Glucose Ketone bodies Not metabolized Acetyl-CoA TCA cycle FED FASTING

Lipid Transport Three Major Lipoprotein Pathways Albumin Chylomicron pathway Delivery of dietary lipid to tissues VLDL Delivery of lipid synthesized by liver to tissues HDL Cholesterol scavenger Albumin Transport of free fatty acids Specialized Carriers Some steroids Some vitamins

Lipoprotien Structure Typical of Chylomicron or VLDL

Lipid Transport The term lipoprotein refers to a particle that contains lipid plus apolipoprotein. The term apolipoprotein refers to a protein without the associated lipid. Example: VLDL is a lipoprotein, and apolipoprotein B-100 is a protein component of VLDL

Lipid Transport Important core apolipoproteins Apolipoprotein B-100 Liver - formation of VLDL Apolipoprotien B-48 Intestine - formation of chylomicrons A shortened version of apolipoprotein B-100 shortened through RNA editing Apolipoproteins A-I and A-II Central protein component of HDL Made in Liver and intestine

Lipid Transport Apolipoproteins added extra-cellularly Apolipoproteins C-I, C-II, C-III C-II is required for the activation of lipoprotein lipase C-III ia an antagonist of lipoprotein lipase C-I is a modulator of cholesterol exchange Apolipoprotein E Involved in recognition and uptake of lipoproteins by the liver Three common alleles (E2, E3, E4) E2/E2 is a risk factor for hyperlipoproteinemia E4 is a risk factor for Alzheimer Disease

VLDL Pathway

VLDL Liver Blood B-100 - Apolipoprotein B-100 TG - Triagylglycerol PL - Phospholipid Ch - Cholesterol ChE - Cholesterol ester TG PL, Ch, ChE VLDL Cholesterol Cholesterol ester

VLDL Liver Blood HDL VLDL B-100 B-100 TG PL, Ch, ChE TG PL, Ch, ChE C

VLDL Liver Blood Lipoprotein Lipase M HDL u s c l VLDL e Adipose o C t e h l e l l i a M u s c l e TG PL, Ch, ChE C HDL E VLDL B-100 TG PL, Ch, ChE E C Adipose Fatty Acid + Glycerol Lipoprotein Lipase

VLDL Liver Blood M HDL u s c l VLDL e IDL Adipose HDL Fatty Acid + n d o C t e h l e l l i a M u s c l e TG PL, Ch, ChE C HDL E VLDL B-100 B-100 TG,PL Ch, ChE TG PL, Ch, ChE E E C IDL Adipose C Fatty Acid + Glycerol HDL

VLDL Liver Blood M HDL u s c l VLDL e IDL Adipose HDL LDL ChE n d o C t e h l e l l i a M u s c l e TG PL, Ch, ChE C HDL E VLDL B-100 B-100 IDL TG,PL Ch, ChE TG PL, Ch, ChE E E C Adipose C ChE Fatty Acid + Glycerol B-100 HDL TG,PL Ch, ChE E LDL

VLDL Liver Blood Liver M HDL u s c l VLDL e IDL LDL Receptor LDL n d o C t e h l e l l i a M u s c l e TG PL, Ch, ChE C HDL E VLDL B-100 B-100 IDL TG,PL Ch, ChE TG PL, Ch, ChE E E LDL Receptor C Adipose LDL C ChE Fatty Acid + Glycerol B-100 HDL TG,PL Ch, ChE Lysosomal degredation E ChE Ch F.A. A.A. Liver Most cells have LDL receptors Bile salts

VLDL Liver Blood Liver LDL Receptor M HDL u s c l VLDL e IDL TG,PL Ch, ChE Liver Blood B-100 E n d o C t e h l e l l i a M u s c l e E TG PL, Ch, ChE C HDL E VLDL B-100 E B-100 IDL TG,PL Ch, ChE TG,PL Ch, ChE TG PL, Ch, ChE E B-100 E LDL Receptor C Adipose LDL C ChE Fatty Acid + Glycerol B-100 HDL TG,PL Ch, ChE Lysosomal degredation E ChE Ch F.A. A.A. Most cells have LDL receptors Liver Bile salts

Intracellular Cholesterol Metabolism LDL receptor LDL

Intracellular Cholesterol Metabolism Lysosome LDL

Intracellular Cholesterol Metabolism Lysosome Amino acids LDL Fatty acids + Glycerol Cholesterol

Liver Cholesterol Metabolism LDL, chylomicron remnants VLDL HMG-CoA reductase HMG-CoA Cholesterol Acyl-CoA 19.5 grams/day Bile salts Cholesterol ester 20 grams/day 0.5 grams/day Bile

Liver Cholesterol Metabolism Inhibition of HMG-CoA reductace and Bile salt readsorption are important therapeutic targets. VLDL Cholesterol inhibits Transcription DNA HMG-CoA reductase Acyl-CoA HMG-CoA Cholesterol Bile salts Cholesterol ester

Periperal Cholesterol Metabolism Tangier Disease: a lack of ABC-A1 HDL Ch to HDL Inhibition of HMG-CoA reductace is an important therapeutic target. ABC-A1 transporter Cholesterol inhibits Transcription DNA HMG-CoA reductase HMG-CoA Cholesterol Cholesterol ester

- Remains in blood To blood Remains in blood NORMAL FAMILIAL HYPERCHOLESTEROLEMIA Remains in blood To blood To blood LDL LDL LDL LDL LDL receptor Lysozyme LDL LDL receptor Lysozyme Cholesterol export LDL LDL receptor Lysozyme Cholesterol export LDL LDL receptor LDL Cholesterol LDL receptor Cholesterol De novo Cholesterol synthesis Nucleus Nucleus - LDL LDL LDL receptor Remains in blood Cholesterol synthesis is limited Cholesterol synthesis is not as limited

Chylomicron Pathway

Chylomicrons B-48 - Apolipoprotein B-48 TG - Triagylglycerol Intestine Lymph B-48 B-48 - Apolipoprotein B-48 TG - Triagylglycerol PL - Phospholipid Ch - Cholesterol ChE - Cholesterol ester TG PL, Ch, ChE Chylomicron Cholesterol Cholesterol ester

Chylomicrons HDL Intestine Lymph Blood B-48 B-48 TG PL, Ch, ChE TG

Chylomicrons M u HDL s c l e Adipose Lipoprotein Lipase o C t e h l e l l i a Intestine Lymph Blood M u s c l e B-48 HDL C TG PL, Ch, ChE E B-48 TG PL, Ch, ChE E C Adipose Fatty Acid + Glycerol Lipoprotein Lipase

Chylomicrons M u HDL s c l e Adipose HDL Intestine Lymph Blood o C t e h l e l l i a Intestine Lymph Blood M u s c l e B-48 HDL C TG PL, Ch, ChE E B-48 Chylomicron TG PL, Ch, ChE E C Adipose B-48 Fatty Acid + Glycerol TG,PL Ch, ChE C E HDL Chylomicron Remnant

(LDL receptor-related protein) Chylomicrons E n d o C t e h l e l l i a Intestine Lymph Blood M u s c l e B-48 HDL C TG PL, Ch, ChE E B-48 TG PL, Ch, ChE E C Adipose B-48 Fatty Acid + Glycerol TG,PL Ch, ChE C E HDL LRP (LDL receptor-related protein) Liver

(LDL receptor-related protein) Chylomicrons E n d o C t e h l e l l i a Intestine Lymph Blood M u s c l e B-48 HDL C TG PL, Ch, ChE E B-48 TG PL, Ch, ChE E C Adipose B-48 Fatty Acid + Glycerol TG,PL Ch, ChE C E Lysosomal degradation HDL ChE Ch F.A. A.A. LRP (LDL receptor-related protein) Liver Bile salts

HDL Pathway Reverse Cholesterol Transport Pathway

HDL Intestine Lymph Blood A PL,Ch Liver

HDL T I S U E LDL A Ch ABC-A1 transporter ChE Liver Intestine Lymph Blood LDL A PL,Ch B-100 TG,PL Ch, ChE E Ch ABC-A1 transporter ChE Liver

HDL T I S U E A Lecithin:cholesterol acyl transferase Ch A LCAT Ch Intestine Lymph Blood A PL,Ch Lecithin:cholesterol acyl transferase B-100 E C Ch A PL,ChE LCAT Ch ABC-A1 transporter ChE Tangier Disease: a lack of ABC-A1 Liver

HDL A A LCAT CETP Cholesterol ester transfer protein ChE TG Liver Intestine Lymph Blood A PL,Ch E C A PL,ChE, TG LCAT CETP Cholesterol ester transfer protein ChE TG TG, PL Ch, ChE E B-100 Liver

HDL A A LCAT CETP Hepatic Lipase H.L. F.A. + Glycerol Liver Intestine Lymph Blood A PL,Ch E C A PL,ChE, TG LCAT CETP Hepatic Lipase H.L. F.A. + Glycerol TG,PL Ch, ChE E B-100 Liver

HDL A A LCAT CETP H.L. SR-B-1 (Scavenger Receptor) Liver Intestine Lymph Blood A PL,Ch E C A PL,ChE LCAT CETP H.L. SR-B-1 (Scavenger Receptor) Liver

Macrophages to “foam cells” Oxidized LDL (not recognized by LDL receptor) Export is limited B-100 TG,PL Ch, ChE SR-A (Scavenger Receptor A) E ABC-A-1 transporter Cholesterol Intracellular accumulation leading to “foam cell” (atherogenic)

Disorders of Lipid metabolism Type I diabetes: Very low insulin: cells act as if starving even though blood glucose is high. Adipose: Fatty acid mobilization up Triacylglycerol synthesis is down Liver: Fatty acid synthesis is down (low glycolysis; low citrate) yet VLDL production is up. Fatty acid oxidation is up Ketone body formation is up: severe ketosis Excess fatty acids go to VLDL formation: high blood lipid.

Dyslipidemias Hypercholesterolemia Hypertirgliceridemia High LDL cholesterol Hypertirgliceridemia High blood triglycerides Combined hyperlipidemia High blood triglycerides and cholesterol Hypoalphalipoproteinemia Low HDL Hypobetalipoproteinemia Low VLDL & chylomicrons

Disorders of Lipid metabolism Type II diabetes: Cells have a greatly reduced sensitivity to the effects of insulin Molecular basis is poorly understood Numerous hormones produced by adipocytes may play a role Effects of obesity PPAR modulates expression of important proteins

Disorders of Lipid metabolism Atheroschlerosis Important risk factors include: High LDL/ HDL ratio High concentration of small dense LDL particles not efficiently taken up by liver targets for oxidation taken up by macrophage Uptake of oxidized lipids by macrophages Cholesterol processing by macrophages

From: Durrington (2003) Lancet 362:717-731

Predisposing alleles and therapeutic targets: Apolipoprotein B VLDL/chylomicron metabolism Apolipoproteins CII & CIII rate of clearance of VLDL Lipoprotein Lipase Rate of clearance of VLDL Apolipoprotein E uptake of chylomicron remnants; LDL uptake Three common Alleles E2/E2 risk factor for hyperlipidemia E4 risk factor for Alzheimer

Predisposing alleles and therapeutic targets: LDL receptor Rate of clearance of LDL Familial hypercholesteolemia Apolipoprotein A1 low HDL Cholesterol ester transfer protein (CETP) HDL stability; LDL metabolism ABC-A1 protein Cholesterol export from cells, particularly macrophage PPARα PPARγ PPARδ