PAI-1 basics

Question 1

What is the primary function of PAI-1?

Answer 1

Inhibition of plasminogen activators.

Question 2

What are plasminogen activators?

Answer 2

Urokinase (UK) and tissue-type plasminogen activator (t-PA).

Question 3

What tissues synthesize PAI-1?

Answer 3

Adipose tissue, cells that store fat ectopically, liver, endothelium, macrophages

Question 4

What do increased levels of PAI-1 activity and concentration lead to?

Answer 4

Hypofibrinolysis and a prothrombotic state.

Question 5

What is PAI-1 a risk factor for?

Answer 5

CVD, myocardial infarction, insulin resistance, MetS and T2DM, visceral fat levels

Question 6

What kind of adipose tissue secretes most PAI-1?

Answer 6

Stromal part of adipose tissue, especially visceral

Question 7

What factors increase or induce PAI-1 expression?

Answer 7

Obesity, metabolic syndrome, Inflammation (TGF-1ß, TNFa), oxidative stress (H2O2), Hyperglycemia, FOXC2, Hypoxia, local Cortisol, endogenous circadian clock,

Question 8

What factors decrease PAI-1 expression?

Answer 8

Antioxidants (NAC), Circadian misalignment in humans,

Question 9

What are secondary function of PAI-1?

Answer 9

Adipose tissue development, potentially contributing to athersoclerosis via cellular matrix degradation, angiogenesis and smooth muscle cell migration

Question 10

How may PAI-1 contribute to obesity and its comorbidities?

Answer 10

Interfering with insulin signalling, adipocyte differentiation and recruitment of macrophages into AT.

Question 11

What factors contribute to PAI-1 synthesis in vitro?

Answer 11

hyperinsulinemia, hyperglycemia, hypertriglyceridemia, elevated FFA

Question 12

What factors contribute to PAI-1 reductions in obese humans?

Answer 12

ACE inhibition,

Question 13

What is special about the 675 4G PAI-1 allele?

Answer 13

prone to obesitz and metabolic syndrome in some studies.

Question 14

What are consequences of PAI-1 KO and pharmacological inhibition?

Answer 14

Protection from fat accumulation (not all studies), insulin resistance, higher number of AT endothelial cells, lower macrophage infiltration of AT, higher metabolic rate, EE, and thermogenesis, improved insulin sensitivity in AT

Question 15

What are effects of PAI-1 overexpression?

Answer 15

adipocyte hypotrophy, reduced feeding efficiency. In older mice: higher insulin levels, higher TAGs (trending) and lower body fat.