The Current Knowledge of the Role of PPAR in Hepatic Ischemia-Reperfusion Injury

Table 1

Effect of strategies that regulate PPAR on hepatic injury, steatosis, and regeneration in experimental models and patients. Angiotensin II: Ang II; choline deficient: CD; epidermal growth factor: EGF; high-fat diet: HFD; insulin-like growth factor 1: IGF-1; methionine choline deficient: MCD; nonalcoholic Steatohepatitis: NASH; peroxisome proliferator-activated receptors: PPARs; polyunsaturated fatty acids: PUFAs; ischemic preconditioning: PC; retinol binding protein-4: RBP4.

PPARα
PPARα activators
Strategies	Time	Effect	Experimental model and patients	Steatosis and hepatic injury	Regeneration
WY-14,643 (30 μmol/kg/d) [17]	3 weeks	↑ PPARα	Obese Zucker rats	↑ β-oxidation of fatty acids	Not evaluated
WY-14,643 (180 μmol/kg/d) [17]	1 week	↑ PPARα	Ob/ob mice	↑ β-oxidation of fatty acids;↓ triglycerides	Not evaluated
WY-14,643 (10 mg/kg) [23, 24]	1 h before ischemia	↑ PPARα	Mice or Rats; warm ischemia (90 min)	↓ hepatic injury	Not evaluated
WY-14,643 (10 mg/kg) [13]	1 h before ischemia	↑ PPARα	Zucker obese rats; warm ischemia (60 min)	↓ hepatic injury	Not evaluated
WY-14,643 (10 mg/kg) [25]	10 days before surgery	↑ PPARα	Foz/foz mice; steatotic livers; warm ischemia (90 min)	↓ hepatic injury	↑ cell cycle entry
Wy-14,643 (0.1%) [37]	5 weeks	↑ PPARα	Mice fed MCD diet	↓ steatohepatitis	Not evaluated
Wy-14,643 (0.1%) [38]	12 days	↑ PPARα	Mice fed MCD diet	↓ steatohepatitis; ↑ hepatic fatty acid oxidation	Not evaluated
Bezafibrate [39]	5 weeks	↑ PPARα	Mice fed MCD	↓ hepatic triglycerides; ↑ hepatic fatty acid oxidation	Not evaluated
Benzafibrate (75 mg/kg) [40]	7 days	↑ PPARα	Rats; partial hepatectomy	↓ availability of fatty acids; sphingolipid synthesis	↓ liver regeneration
PC (5 min/10 min) [13]	Immediately before ischemia	↑ PPARα	Obese Zucker rats; warm ischemia (60 min)	↓ hepatic injury	Not evaluated
n-3 PUFA (EPA (270 mg/kg) and DHA (180 mg/kg)) [28]	7 days	↑ PPARα	Sprague-Dawley rats; warm ischemia	↓ hepatic injury, inflammation, and oxidative stress	Not evaluated
EPA (2700 mg/d) [41]	1 year	↑ PPARα	NAFLD patients	↓ steatosis, hepatic injury, necroinflammation, and oxidative stress	Not evaluated
n-3 PUFA (1 g/day) [42]	1 year	↑ PPARα	NAFLD patients	↓ steatosis, hepatic injury, and necroinflammation	Not evaluated
n-3 PUFA (2 g/day) [43]	6 months	↑ PPARα	NAFLD patients	↓ steatosis, hepatic injury, necroinflammation, and hepatic injury	Not evaluated
n-3 PUFA (2 g, 3 times daily) [44]	24 weeks	↑ PPARα	NAFLD patients with hyperlipidemia	↓ steatosis and hepatic injury	Not evaluated
Ω-3 FA (5 mL, thrice daily) [45]	24 weeks	↑ PPARα	NAFLD patients with dyslipidemia	↓ steatosis and hepatic injury	Not evaluated
Atorvastatin (20 mg/daily) [45]	24 weeks	↑ PPARα	NAFLD patients with dyslipidemia	↓ steatosis and hepatic injury	Not evaluated
Orlistat (120 mg, thrice daily) [45]	24 weeks	↑ PPARα	NAFLD patients with dyslipidemia	↓ steatosis and hepatic injury	Not evaluated
PPARα knockout
Strategies	Time	Effect	Experimental model	Steatosis and hepatic injury	Regeneration
PPARα-knockout [23]	—	↓ PPARα	PPARα-null mice Warm ischemia (90 min)	↑ hepatic injury	Not evaluated
PPARα-knockout [46]	—	↓ PPARα	PPARα-null mice fed HF diet	↑ hepatic β-oxidation	Not evaluated
PPARα-knockout [47]	—	↓ PPARα	PPARα-null mice Partial hepatectomy	Not evaluated	↓ liver regeneration
PPARγ
PPARγ activator
Strategies	Time	Effect	Experimental model	Steatosis and hepatic injury	Regeneration
Rosiglitazone (10 mg/kg) [6]	30 min before ischemia	↑ PPARγ	PPAR𝛾^± mice	↓ hepatic injury	Not evaluated
Rosiglitazone (2.5 μmol/kg/d) [17]	1 week	↑ PPARγ	Ob/ob mice	↓ triglycerides	Not evaluated
Rosiglitazone (3 mg/kg/day) [48]	5 weeks	↑ PPARγ	PPARγ ^fl/fl mice fed HFD diet	↑ steatosis	Not evaluated
Rosiglitazone (1 mg/kg/day) [49]	12 weeks	↑ PPARγ	Obese C57BL/6J mice	↑ steatosis	Not evaluated
Rosiglitazone (10 mg/kg) [50]	2 days before surgery	↑ PPARγ	Mice partial hepatectomy	Not evaluated	↓ hepatic regeneration
Troglitazone (0.1%) + adPPARγ [51]	adPPARγ (5th day) troglitazone (5 days)	↑ PPARγ	PPARα-null mice fed CD diet	↑ steatosis	Not evaluated
Pioglitazone (500 μg/Kg) [52]	8 weeks	↑ PPARγ	Rat fed liquid diet + alcohol	↓ liver injury	Not evaluated
Pioglitazone (30 mg) [53]	96 weeks	↑ PPARγ	Patients with NASH	↓ steatosis	Not evaluated
Pioglitazone (25 mg/kg/day) [54]	5 days before surgery	↑ PPARγ	KK-A^Y, mice partial hepatectomy	Not evaluated	↑ hepatic regeneration
Pioglitazone (20 mg/kg) [7]	1.5 h before ischemia	↑ PPARγ	Mice Warm ischemia (60 min)	↓ hepatic injury	Not evaluated
Ang II blockers Captopril (100 mg/kg) or PD123319 (30 mg/kg) [36]	Immediately before ischemia	↑ PPARγ	Obese Zucker rats; warm ischemia (60 min)	↓ hepatic injury	Not evaluated
EGF and IGF-1 (10 μg/L) [34]	24 h in UW solution	↑ PPARγ	Obese Zucker rats; isolated liver perfused (24 h cold ischemia)	↓ hepatic injury	Not evaluated
EGF (100 μg/Kg) [35]	3 doses (every 8 h) starting before surgery	↑ PPARγ	Obese Zucker rats; warm ischemia (60 min)	↓ hepatic injury	Not evaluated
IGF-I (400 μg/Kg) [35]	2 doses (every 12 h) starting before surgery	↑ PPARγ	Obese Zucker rats; warm ischemia (60 min)	↓ hepatic injury	Not evaluated
Adenovirus PPARγ + rosiglitazone (50 mg/kg/day) [55]	8 weeks	↑ PPARγ	C57BL/6J mice fed MCD diet	↓ steatohepatitis and fibrosis	Not evaluated
PC (5 min/10 min) [36]	Immediately before ischemia	↑ PPARγ	Obese Zucker rats; warm ischemia (60 min)	↓ hepatic injury	Not evaluated
PPARγ inhibitor
Strategy	Time	Effect	Experimental model	Steatosis and hepatic injury	Regeneration
GW9662 (1 mg/kg) [14]	1 h before surgery	↓ PPARγ	Liver transplantation (6 h cold ischemia)	Does not change in hepatic injury	Not evaluated
GW9662 (1 mg/kg) [14]	1 h before surgery	↓ PPARγ	Steatotic liver transplantation (6 h cold ischemia)	↓ hepatic injury	Not evaluated
GW9662 (1 mg/kg, 3 times/week) [55]	8 weeks	↓ PPARγ	C57BL/6J mice fed MCD diet	↑ steatohepatitis, fibrosis and hepatic injury	Not evaluated
RBP4 (150 μg/kg) [14]	30 min before surgery	↓ PPARγ	Steatotic liver transplantation (6 h cold ischemia)	↓ hepatic injury	Not evaluated
PC (5 min/10 min) [14]	Immediately before ischemia	↓ PPARγ	Steatotic liver transplantation (6 h of cold ischemia)	↓ hepatic injury	Not evaluated
PPARγ inhibitor
Strategies	Time	Effect	Experimental model	Steatosis and hepatic injury	Regeneration
PPARγ-knockout [56]	—	↓ PPARγ	Liver-specific PPARγ-null mice	↓ steatosis	Not evaluated