Lipid Metabolism 4 (2)

Intestinal digestion of dietary TG

TG--> colipase, lecithin, pancreatic lipase, HOH, 2 FAs--> B-monoglyeride (B-MG or 2-MG)

occurs outside the cell and then TG gets reformed back to TG inside the cell

Orlistat

-anti-obesity
-blocks pancreatic lipase, halts TG to B-monoglyceride (B-MG or 2-MG)

the breakdown product of TG absorbed into the intestinal cells

B-MONOGLYCERIDE
(B-MG or 2-MG)

inside the intestinal epithelial cell what happens to B-MG

B-MG + 2 FA~S-CoA--> Fatty acyl CoA Transferase + 2 CoASH --> TG

The fate of the vast majority of cholesterol

bile salts

others go to membranes and steroid hormones

Endogenously made lipids: Sites of cholesterol synthesis and percentage of total Endogenously made pipids

1) liver- MAJ site 50%
2) intestine 15%
3) extrahepatic (skin) 35%

major site of endogenously made lipids

liver

Synthesis of mevalonic acid from HMG CoA--step in cholesterol synthesis

HMG CoA--> HMG CoA reductase + NADPH2 --> Mevalonic Acid + CoASH + 2NADP

This is the REGULATORY STEP in the cholesterol synthesis

The enzyme that catalyzes the synthesis mevalonic acid from HMG CoA--the regulatory step in cholesterol synthesis

HMG CoA reductase

how do statins halt the synthesis of cholesterol?

By inhibiting HMG CoA Reductase

This stops the synthesis of mevalonic acid from HMG CoA

esterification of cholesterol (inside intestinal epithelial cell)

cholesterol + fatty acyl CoA --> ACAT--> cholesteryl ester (CE) + CoASH

ACAT= Acyl (fatty) Cholesterol Acyl (fatty) Transferase`

NPC1L1 transporter

transports dietary cholesterol from the lumen of the gut to the intestinal epithelial cell

fatty acyl transferase

catalyzes reaction of B-monoglyceride + 2 fatty acyl--> triglyceride

occurs inside the intestinal epithelial cell

formation and secretion of chylomicrons

-occurs in intestinal epithelial cells
-assembly in ER and golgi
-TG from smooth-ER
-ApoB-48 from rough ER
-both combine in Golgi to make nascent chylomicrons

what proteins get transferred from HDL to chylomicrons--leading the maturation of nascent chylomicrons to mature chylomicrons?

ApoCII and ApoE

Major Site of TG synthesis

Liver

TG synthesis in the cells RXN

Glycerol + 3FAs --> TG --> VLDL

Major apolipoproteins and which lipoprotein they belong to (excluding HDL)

-Apo B-48= chylomicron
-Apo B-100 = VLDL, LDL, & IDL

VLDL and LDL Life Cycle

1) Liver secretes nascent TAG-rich VLDL particles
2) Apo C-II and Apo E are transferred from HDL to nascent VLDL
3) Extracellular lipoprotein lipase, activated by apo C-II, degrades TAG in VLDL
4) Apo C-II and apo E are returned to HDL
5) LDL binds to specfic receptors to extrahepatic tissues and on the liver where they are endocytosed

VLDL in liver
LDL in blood

How does NPC1 inhibitors work as an anti-cholesterol drug?

NPC1 transports cholesterol from lumen into intestinal epithelial cell. An inhibition of this would block and halt intestinal absorption of cholesterol

How does ABC1 mutation lead to Tangier disease/low HDL?

The ABC1 mutation inhbits ABC1 transporter, preventing release of cholesterol into blood from intestinal epithelial cell. HDL needs blood cholesterol to form and Tangier disease is charecterized by low levels of HDL in blood. Thus, inhibiting ABC1 transporters lowers HDL and causes Tangier disease.