Peroxisome Proliferation Activated Receptors And Disease

Question 0

Therapy for T2DM

Answer 0

1) diet and exercise
2) sulphanylureas -> act on R’s on beta cells-> stimulate insulin release
3) insulin
4) Metformin->reduces hepatic glucose output -> 25% of BG is from liver gluconeogensis

Question 1

Obesity and T2DM

Answer 1

Increased adipose:lean body mass ration
Imbalance of secretions from adipose-> lipotoxicity-> inflammatory response and insulin resistance
FFAs and cytokines-> increased liver glucose release as body thinks it’s starving
Insulin resistance-> no glucose in tissues-> starvation-> increased lipolyisis
-> high blood glucose
-> glycosylated Hb
Initially beta cells compensated, get tired-> hypoinsulinemia

Question 2

Perioxisome proliferator activated receptors

Answer 2

Steroid hormone nuclear receptor family
Liver metabolism
Major form directly regulates the activity of genes that are involved in fatty acid uptake and beta and w oxidation of fatty acids-> PPARa
Ligand activated transcription factors
Heterodimeric complex
Activated by increased fat in the liver-> fat accumulates in mice liver without it
-> not enough substrate to make glucose with
Antagonists can cause proliferation of perioxisomes

Question 3

Nuclear receptors off state

Answer 3

Compressor complex binds in absence of a ligand to AF2 regions on the nuclear receptor
DNA/ligand binding domain remains open
-> keeps the complex in a repressed state -> DNA wound round chromatin-> repressive chromatin structure-> RNA polymerase can’t access it

Question 4

Nuclear receptors on state

Answer 4

Ligand binds to ligand receptor-> conformational change -> co activator complex can now bind-> chromatin unravels-> RNA polymerase (activated by co activator) can now access-> gene turned on

Question 5

Metabolic effects of PPARa activation

Answer 5

Liver-> fatty acid oxidation-> ACO,ACS
Muscle-> lipid metabolism-> increased LPL (lipoprotein lipase)
Agonise in hyperlipideamia

Question 6

PPARy metabolic effects

Answer 6

Fat-> adipogenesis via AP2
Liver-> glucose control-> increase GLUT 4
-> lipid metabolism-> LPL
Antidiabetics
Primary expression in adipose-> GLUT 4 increase/activates lipoprotien adipogenesis-> lipase-> increased adipose-> weight gain

Question 7

PPARa activation and insulin sensitivity

Answer 7

Increased gene expression of LPL in hepatocytes -> more conversion of VLDL to FA -> metabolised in muscle, stored as TG in adipose
Decreased gene expression of ApoC III -> inhibition of apo B
Increased gene expression of FAT-> increased FA absorption in to muscle
Increased FATP-> increased FA in to adipose
Liver:
Increase FAT-> FA from adipose to liver
Increased ACS-> increased FA to FA CoA for oxidation
Increased FAS-> acetoy CoA to FA for combination with VLDL
-> fat is taken in to liver/ muscle and oxidised-> decreased insulin resistance as less lipotoxicity
Well tolerated-> don’t work well

Question 8

PPARy and insulin sensitivity

Answer 8

Adipose-> increased fat synthesis, decreased lipolyisis-> decreased FFAs-> decreased cytokine release from liver and pancreas
Increased glucose disposal-> increase enzymes of glucose signalling -> increased glucose uptake/overcomes insulin resistance
-> fat is in adipose in stead of liver -> deceased insulin resistance
Indirect-> fat, liver, skeletal muscle -> decreased glucose,increased insulin sensitivity, decreased TAG, increased HDL
Direct-> vascular and inflammatory cells-> decreased cytokines, Chemokines, increased cholesterol efflux, decreased adhesion molecules
-> decreased inflam-> decreased atherosclerosis

Question 9

PPARa and y and heart disease in diabetes

Answer 9

Alpha activated by -> fibrates, TG/HDL
Gamma-> TZDs, insulin sensitising
Indirectly-> fat, liver, skeletal muscle-> decrease glucose, increased insulin sensitivity, decrease TG, increase HDL -> decreased inflammation-> decreased atherosclerosis
Directly-> vascular and inflam cells-> decreased cytokines, Chemokines, increased cholesterol efflux, decreased adhesion moleclues-> decreased inflammation-> decreased atherosclerosis

Question 10

Problems with PPARs

Answer 10

PPARy is expressed in lots of tissues-> widespread effects
Rosiglitazone-> increased risk of cv events
Dioglitazone-> bladder cancer
Troglitazone-> liver toxicity

Question 11

Dual PPAR agonists

Answer 11

Fibrates-> PPARa-> decreased TG, increased HDL
TZDs-> PPARy-> decreased glucose, increased insulin sensitivity
-> do both
Miraglitazar-> increased and worse cv events

Question 12

Diabetes prevention programme

Answer 12

-> diet and exercise targets
>7% weight loss
> 150 min moderate intensity exercise per week