Zaidi: Lipids and Lipoproteins Flashcards
TG
Triacylglycerols
Major storage form of fatty acids
TG composition
one glycerol group and three fatty acid chains
Dietary TG is processed where
in the intestinal cells
De Novo TG synthesis occurs
in liver hepatocytes and adipocytes
TG Synthesis in Intestinal Cells: sequence
TGs are broken down in the lumen of the intestine into
1) FAs
2) 2-monoacylglycerol
Both are transported across the epithelia. Inside, FAs are converted to
1) Fatty acyl CoA
and 2-monoacylglycerol is converted into
1) Diacylglycerol.
Fatty acyl CoA and diacylglycerol are combined to produce Triacylglycerols (TGs), which are packaged with
apolipoproteins and other lipids to form CHYLOMICRONS
After TGs are reassembled in the intestinal cell, what happens
they are combined with apoproteins and lipids = chylomicrons
In the liver, there are a number of events leading to TG synthesis: what are the “big” initial steps
Glucose is converted into DHAP, which is reduced and combined with an oxidized form of glycerol to form Glycerol-3-P.
G3P is combined with fatty acyl CoA to form a number of intermediates, eventually TG
fatty acyl coA is responsible for
activating fatty acids that have been transported from the lumen into fatty acyl CoA inside the cell
Glucose is converted into G3P by
G3P Dehydrogenase
Hepatocyes
Glycerol is converted into ___ by _____
Glycerol 3P by Glycerol Kinase
Hepatocytes
In the liver, de novo FAs are initially
converted into FA-CoA by FA-CoA Synthase, eventually combined with G3P, and subsequently comverted into TG and repackaged into chylomicrons
TG synthesis in adipocytes: what two processes occur before production of a TG happens?
Glucose is broken down via glucose and transformed into G3P.
FA is broken down into FA-CoA
G3P and FA-Coa are combined to eventually form TG and stored
What enzyme activates FA into FA-CoA?
FA-CoA Synthase
VLDL is produced in the
hepatocyte and released into the blood
Capillary Lipoprotein Lipase
Chylomicrons and LDLP are delivered to the adipocyte.
CLPL break these down into FA’s
found in the adipocyte:
breaks down lipoproteins and VLDL to form glycerol and FAs. these are internalized and used for TG formation
In which cell is glucose converted to glycerol by Glycerol kinase?
Hepatocyte. Does not happen in the adipose cell, which uses glycolysis followed by G3P Dehydrogenase to produce Glycerol-3-P
which enzyme is used by hepatocytes to form glycerol but not in adipocytes?
glycerol kinase
What is the source of glycerol in the hepatocyte
it’s moving around freely because of the breakdown of TG but also because of glycolysis
where is glycerol kinase found?
the liver only
CLPL
made by adipocyte but RELEASED out of the adipocyte
breaks down VLDL and chylomicrons into the FAs, which are then used to form TGs inside the cell
where is the source of glycerol in adipocyte?
glycolysis, but lacks the glycerol kinase
Insulin acts on which enzyme in the adipocyte?
capillary lipoprotein lipase
What does Insulin mobilize in adipocytes?
the breakdown of VLDL and chylomicrons by capillary lipoprotein lipase
TG are broken down where
adipocytes
why don’t hepatocytes or intestinal cells break down TG?
they deliver TGs to different locations, but its hepatocytes that are primarily responsible for breaking down the TGs
What three enzymes do we find in the adipocyte involved in TG breakdown (just name them)
hormone sensitive lipase
lipoprotein lipase
monoacyl-glycerol lipase
hormone sensitive lipase is activated ( -/+) by
norepinephrine and epinephrine and glucagon (+)
insulin (-)
hormone sensitive lipase does what?
mobilizes TGs into FA and DAG
Lipoprotein Lipase is found where and does what
adipocyte
converts DAG into an FA and a monoacylglycerol
monoacyl-glycerol lipase does what
converts monoacyl glycerol into FA and glycerol
FAs in the adipocyte leave according to size
shorts FAs are soluble and diffuse out, long FAs are combined with albumin to exit
HSL is activated directly by
Hormone Sensitive Lipase is activated by phosphorylation by PKA
PKA does what
“ultimately” activates HSL
is activated by hormones via cAMP (GCPR) signaling cascade
it phosphorylates Hormone Sensitive Lipase (HSL) to initiate TG breakdown
Hormone Sensitive Lipase is inactivated by
Protein Phosphatase 1 (DP1)
How does DP1 act in the cell?
it is INACTIVATED by insulin
Epinephrine and Glucagon promote
lipolysis
Insulin inhibits
lipolysis
Glucaon is released in response to
hunger
Epinephrine is released in response to
exercise
Insulin is released in response to
high carb meal
Perilipin
family of proteins that coats lipids in adipocytes and muscle cells
REGULATED BY PKA
regulates LIPOLYSIS by blocking physical access to HSL
overexpression leads to inhibition of lipolysis and knock out the revers effect
target of anti-obesity drugs
what does perilipin do exactly? who controls it?
it blocks physical access HSL
PKA
Perilipin coats
lipid droplets and prevents HSL from activating their degradation
Synthetic FATs
Olestra
what are synthetic fats made from?
synthetic fats made of sucrose backbone with 6-8 fatty acids
no absorbed in small intestine
no calories
excreted out in stool
absorb vitamins A, D, E, K
high amounts of olestra
cause deficiency in these vitamins
abdominal cramps, bloating and diarrhea
Olestra
synthetic fatty acid that humans lack an enzyme to breakdown
absorbs K.A.D.E, so depletes you of vitamins
causes bloating, diarrhea etc
sucrose with a backbone of 6-8 fatty acids
Lipoproteins serve what purposes,
transport form for TG, cholesterol, and fat soluble vitamins
Structure of the lipid: outershell and inner shell
outer: monolayer of phospholipids, free cholesterol, apoproteins
inner hydrophobic TGs, cholesterol esters
ACAT
Acyl CoA Acyl Transferase (ACAT)
ACAT
Transfers acyl groups to cholesterol to make them hydrophobic (cholesterol —> cholesterol-estor)
cholesterol ester
5 different types of lipoproteins
- chylomicron
- VLDL
- IDL
- LDL
- HDL
Chylomicrons
largest and least dense of the lipoproteins
High TG content
ApoB-48 and ApoC-II and ApoE
What the three surface apoproteins associated with chylomicrons?
ApoB-48
Apo-E
Apo-C-II
exogenous, formed from dietary fats
VLDL
ApoB-100
ApoE
ApoC-II
IDL
ApoB-100
ApoE
LDL
ApoB-100
HDL properties
smallest, most dense, high protein and phospholipid content
swelling in LNs found in infections and cancer
non-Hodgkin lymphoma
Apolipoprotein functions
Structural, Transport, Cofactors for Enzymes
Apolipoproteins function: structural
stabilizes lipoproteins
Apolipoproteins function: transport
redistribution of lipids between tissues
Apolipoproteins finction: coenzymes
Apo-CII activates LPL
Type I Hyperchylomicronemia
AKA hyperchylomicronemia
Deficiency in Apo-C-II OR
defective lipoprotein lipase
the effect is to elevate chylomicrons and TGs
inability to hydrolyze TAGs, chylomicrons, VLDL
When is Type I Hyperchylomicronemia diagnosable?
Primary LPL deficiency in infancy
ApoC-II deficiency, post adolescence
What is a treatment for Type I Hyperlipoprotenemia?
low fat diet
Clinical symptoms of type I hyperlipoprotenemia
abdominal pain, acute pancreatitis
Type II hyperlipoproteinemia
AKA familial hyperchylomicronemia (FH)
Type II hyperlipoproteinemia: Cause
defects in LDL uptake via LDL receptor
Type II hyperlipoproteinemia: what is impaired?
LDL receptor fails to recognize ApoB 100 on LDL
Type II hyperlipoproteinemia: long term problems
LDL adding to athersclerosis
Type II hyperlipoproteinemia: genetics
autosomal dominant inheritance
Normal cholesterol is
130-200 mg/dl
cholesterol for heterozygous Type II hyperlipoproteinemia is
300-500 mg/dl
homozygous for Type II hyperlipoproteinemia is
> 800 mg/dl
untreated homozygous die from
coronary heart disease CAD befroe teenager years
untreated homozygous develop CAD by
age 40
Two sources of G3P in the liver
when glycerol kinase phosphorylates glycerol or when DHAP is reduced
insulin stimulates adipocytes to secrete
capillary lipoprotein lipase, which recognizes ApoC-II in chylomicrons and VLDL
PKA is activated by ___ which allows the PKA to do what?
glucagon, phosphorylate HSL
Protein Phosphatase 1 does what?
it dephosphorylates HSL
PP1 is activated by
insulin
Good Cholesterol: content and Apos
high protein and phospholipid content
ApoA-I
ApoE
ApoC-II
Chylomicron processing
- nascent chylomicrons are synthesized in the liver and transported via lymphatics to the bloodstream
- mature chylomicron is produced when HDL adds ApoC -II and ApoE
- Chylomicron ApoC-II is recognized by CLPL, which hydrolyzes TGs into glycerol and FAs: ApoC is released back to HDL
- FAs and glycerol are endocytosed by binding ApoE
abetalipoproteinemia
lack of ApoB’s
VLDL, IDL, LDL prcoessing
- VLDL is released by the liver. ApoCII is recognized by CLPL, breaks down VLDL. ApoCII released back to HDL.
- The remaining molecule is IDL. Cholesterol in the IDL is released via the receptor recognition of ApoE.
- IDL loses more TGs and via hepatic lipoprotein lipase s well as ApoE —> becomes LDL
- LDL delivers cholesterol to the liver and peripheral tissues via binding of ApoB-100 to LDL receptors on targets cells etc.
HDL processing
- HDL is produced in the liver
- it is released and picks up cholesterol from tissues
- is esterfies cholesterol
- it exchanges estrified cholesterol with VLDL, IDL, LDL for TGs and phospholipids
- it exchanges and receives ApoE and ApoC-II with VLDL, IDL, LDL
- VLDL, IDL, LDL deliver cholesterol to liver
Type I Hyperlipoproteinemia
Cause, Effect
Deficiency in ApoC or LPLs
Surge of TGs and Chylomicrons
Type II Hyperlipoproteinemia
Cause Effect
Deficiency in LDL receptor
Surge in Cholesterol, TGs, LDL, VLDL
Type III hyperlipoproteinemia
AKA familial dysbetalipoproteinemia
Defect in ApoE
Surge in cholesterol, Chylomicon remnants, TGs, IDL
Type IV hyperlipoproteinemia
aka familial hypertriglyceridemia
Reduction in catabolism of VLDLs or increase in their synthesis
Surge in cholesterols (slightly), TGs, VLDL
Type V hyperlipoproteinemia
combination of I and IV
surge in chylomicrons, VLDL, TGs but normal LDL
Tangier disease
defect in transporter that supports cholesterol pickup by nascent HDL
abetalipoprotenmia
Lack of ApoB’s
decrease in chylomicrons and VLDL, IDL, LDL
hpoalphaliporproteinemia
accelerated catabolism of ApoA I an II
decrease in HDL
HDL’s beneficial effects
because of its ability to receive cholesterol from peripheral tissues, HDL increase is considered to confer benefits like reduced CAD.
HDL is increased by exercise, smoking cessation, moderate alcohol consumption, and antihyercholestermic drugs and weight loss
HDL levels are low in
smoking, progestin, androgens, beta blockers, and high intake of PUFA (omega-6)
Statins
statins mimic the structure of HMG CoA and Mevalonate (substrate and product of HMG Co-A Reductase
HMG CoA Reductase
rate limiting enzyme in cholesterol biosynthesis
Statins are competitive inhibitors of HMG CoA Reductase
enhance transcription of LDL receptor
more uptake into hepatocytes, lowering plasma levels w
Lovastatin
targets HMG CoA Reductase
what is the rate limiting step in cholesterol biosynthesis?
HMG-CoA reductase converting HMG-CoA along with NADPH reducing HMG-CoA into Mevalonic Acid. Mev is eventually converted into cholesterol
