Lecture 17: Lipids and Lipoproteins Flashcards
Major storage form of FA’s?
TAG’s
TAG’s are made de novo where?
Hepatocytes and Adipocytes
Dietary TAG’s are processed where?
Intestinal cells
Dietary TAG’s are broken down into what in the intestinal lumen?
MAG and FFA
Resynthesizing TAG’s by intestinal cells uses what as the backbone and which enzyme?
MAG as the backbone; Fatty acyl CoA synthetase
TAG’s made by intestinal cells are packaged with apolipoproteins and other lipids to form?
Chylomicrons
Where are chylomicrons released and enter blood via?
Lymphatic system and enter blood via thoracic duct
What are the starting molecules for TAG synthesis in the liver?
Glucose + Glycerol
Glucose and glycerol combine to form the backbone for TAG synthesis in liver, which is?
Glycerol 3-phosphate
What enzyme is ONLY present in the liver?
Glycerol kinase
Fatty acids in hepatocytes are synthesized how?
De novo
TAGs packaged with apolipoproteins and other lipids from hepatocytes form?
Very Low Density Lipoproteins (VLDL)
Where are VLDL’s released?
Bloodstream
Source of the glycerol (G-3-P) backbone in adipocytes?
Glucose
What are the source of FA’s for TAG synthesis in adipocytes?
Come from the breakdown of Chylomicrons and VLDL’s
What cuts the TAG’s from VLDL’s and Chylomicrons, releasing the FA’s for adipocytes to use in resynthesizing TAG’s?
Capillary lipoprotein lipase
What happens to the TAG’s made by adipocytes?
Stored in adipocytes
3 major lipases for breakdown of TAGs?
1) Hormone sensitive lipase (HSL)
2) Lipoprotein lipase (LPL)
3) Monoacylglycerol lipase (MAG lipase)
Long chain fatty acids require what for transport?
Complexed with Albumin
HSL activity is modulated by?
Phosphorylation
The 2 major signals that promote mobilization of TAGs; hormones involved?
1) Hunger - glucagon
2) Exercise - epinephrine
What inhibits the mobilization of TAGs?
Insulin inhibits lipolysis (FED STATUS)
What acts before HSL and activates it during lipolysis?
ATGL - adipose triglyceride lipase
What is Perilipin?
Family of proteins that coat lipid droplets in adipocytes and muscle cells.
How does Perilipin regulate lipolysis?
By controlling physical access to HSL (surrounds the lipid droplet)
In mice with overexpression of Perilipin what is observed?
Inhibition of lipolysis
In mice with Perilipin knocked out what is observed; significance?
Increases lipolysis; target of obesity tx
Perilipin is regulated by, how?
PKA, phosphorylation causes release of lipid droplet so it can associate with HSL, promoting lipolysis.
Function of lipoproteins?
- Serve as transport vehicle for cholesterol, TAGs, and fat soluble vitamins
- Contribute to the metabolism of lipids
What is contained in the outer shell of lipoproteins?
Monolayer of phospholipids, free cholesterol, and apolipoproteins
What is contained in the inner core of lipoproteins?
Packed with hydrophobic TAG’s, cholesterol esters
What are the 5 types of lipoproteins?
1) Chylomicrons
2) VLDL
3) IDL
4) LDL
5) HDL
Properties of Chylomicrons?
- Largest
- Least dense
- High TAG content
Function of ApoB-48 on chylomicron?
Facilitates transport
Function of ApoC-II on chylomicron?
Activates capillary lipoprotein lipase which degrades the TAG
Function of ApoE on chylomicron?
Facilitates uptake into liver (binds receptor)
What makes LDL worse than VLDL?
LDL contains less TAG’s and more cholesterol
Properties of HDL?
- Smallest
- Most dense
- High protein and phospholipid content
What can HDL do with ApoC-II and ApoE?
Can exchange with other lipoproteins allowing them to be more active
When a chylomicron is first assembled with dietary lipids in the intestine what is it referred to, why?
- Nascent Chylomicron
- Doesn’t have ApoE or ApoC-II
When a chylomicron becomes mature what happens to it?
Acted on by capillary LPL, which hydrolyzes TAG’s into glycerol and FFA’s, creates a Chylomicron remnant
What happens to a chylomicron remnant?
Endocytosed by the liver via binding of ApoE to its receptor
VLDL’s are assembled in liver and already contain?
ApoC-II and ApoE
Describe what happens during the processing of VLDL in the blood?
VLDL is acted on by capillary LPL, hydrolyzing the TAG’s into FFA and glycerol. ApoC-II is released back to HDL, and IDL remains
What happens to cholesterol in IDL?
Cholesterol in IDL is delivered to the liver via bind of ApoE to IDL receptors on hepatic cells.
How does IDL lose more TAG’s; becomes?
Via action of hepatic lipoprotein lipase; becomes LDL
What happens to LDL?
Delivers cholesterol load to the liver and peripheral tissue via binding of ApoB-100 to LDL receptors on target cells
Function of ApoB-100?
Binds the LDL receptor on cells, allowing for the cell to internalize the LDL
What happens upon internalization of LDL by cells?
LDL is sent to lysosomes where it is chopped up, and the raw materials are released
What happens when there are defects in the LDL receptor?
LDL is NOT taken up and will sit in blood forming plaques (familial hyperlipidemia)
Where is HDL synthesized?
Liver and Small intestines
What does nascent HDL do?
Picks up cholesterol from peripheral tissues
What enzyme allows for the esterification of cholesterol inside of HDL?
Lecithin cholesterol acyl transferase
Function of cholesterol ester transfer protein?
Allows for HDL to transfer cholesterol esters to VLDL, IDL, and LDL in exchange for TAG’s and phospholipids
HDL has the ability to reverse what?
Cholesterol transport from peripheral tissues to liver
What are some recently discovered properties of HDL?
Antioxidant and Anti-inflammatory
Type I Hyperlipoproteinemia (aka hyperchylomicronemia) is caused by?
A deficiency in Lipoprotein Lipase (LPL) or ApoC-II
Type I Hyperlipoproteinemia effects?
Inability to hydrolyze TAG’s in chylomicrons and VLDL
A primary LPL deficiency manifests when?
Infancy (more serious)
ApoC-II deficiency manifests when?
Post-adolescence
Type I Hyperlipoproteinemia follows what genetic inheritance pattern?
Autosomal recessive (both alleles need to be bad)
Clinical symptoms and tx for Type I Hyperlipoproteinemia?
Sx: Abdominal pain, acute pancreatitis, cutaneous eruptive xanthomas
Tx: Low fat diet
Plasma TAG levels will be at what level in Type I Hyperlipoproteinemia?
> 1000 mg/dL (very high)
Type II Hyperlipoproteinemia (aka hypercholesterolemia) is caused by?
Defects in uptake of LDL via LDL receptor; impaired ability to recognize ApoB-100 on LDL
75% of the clearance of LDL in plasma is accomplished via?
Receptor mediated endocytosis via LDL receptor
Type II Hyperlipoproteinemia follows what type of inheritance pattern?
Autosomal dominant (only need one bad allele)
Heterozygous Type II Hyperlipoproteinemia manifests when and correlates with what cholesterol level?
- In middle age
- 300-500 mg/dL
Homozygous Type II Hyperlipoproteinemia manifests when and correlates with what cholesterol level?
- In teens
- >800 mg/dL
If untreated homozygous Type II Hyperlipoproteinemia patients will die of?
Coronary artery disease (CAD) before teenage years
Tx for heterozygous Type II Hyperlipoproteinemia?
Statins, diet, and bile acid binding resins
Tx for homozygous Type II Hyperlipoproteinemia?
LDL apheresis and liver transplantation
