Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPARγ Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease

Table 1

Main findings extracted from selected scientific papers supporting the prosteatogenic role of FAT/CD36 in the MoA from PPARγ dysregulation to NAFLD.

Species	PPARγ related strain characteristics	Diet	Experiment type	Gene manipulation	Pharmacological treatment		Endpoints			Reference
					Agent	Type	PPAR𝛾	CD36	NAFLD biomarkers
Human	NASH patients							+	+	[15]
Mouse	Wild type	HFD					+		+	[16]
	Liver PPAR𝛾 deficient line	HFD					0		0
	Wild type	CD		PPAR𝛾 transfected			+	+	+
	Liver PPAR𝛾 deficient line	CD		PPAR𝛾 transfected			+	+	+
Mouse			Hepatocytes	PPARγ transfected			+	+	+
					Rosiglitazone	Synthetic agonist	+	++	++
					Palmitate	Endogenous metabolite	+	++	++
Mouse	Functional PPARγ	HFD					+	+	+	[17]
	PPAR𝛾 knockout	HFD					0/+	0/+	0/+
Mouse	Functional PPARγ		Tissue slices		Oleic acid	Endogenous agonist			+
	Functional PPARγ				Rosiglitazone	Synthetic agonist			+
	PPARγ knockout				Oleic acid	Endogenous agonist			0
	PPARγ knockout				Rosiglitazone	Synthetic agonist			0
	Functional PPARγ		Hepatocytes		BADGE	Synthetic antagonist			−
	Functional PPARγ				Oleic acid + BADGE	Endogenous agonist +Synthetic antagonist			𝟎/+
Mouse	Insulin-resistant mice	CD					+	+	+	[18]
	Control mice	CD			Pioglitazone	Synthetic agonist			0
	Insulin-resistant mice	CD			Pioglitazone	Synthetic agonist	0	+	++
Mouse	Wild type	HFD-safflower oil					0/+	0	0/+	[19]
	Wild type	HFD-butter					+	+	+
	Wild type	HFD-safflower oil		PPAR𝛾2 knockdown			+	0/+	0/+
	Wild type	HFD-butter		PPAR𝛾2 knockdown			+	0/+	0/+
	Wild type	CD		PPAR𝛾 transfected			+	+	+
Mouse	JAK2L-tyrosine kinase deficient	CD					+	++	++	[20]
	Wild type	CD			GW9662	Synthetic antagonist	0	0	0
	JAK2L-tyrosine kinase deficient	CD			GW9662	Synthetic antagonist	+	+	+
Mouse	Liver SMS2-overexpressing transgenic line	CD						+	0/+	[21]
	lSMS2-deficient knockout line	CD						−	0/−
	Wild type	HFD					1	1	+
	Liver SMS2-overexpressing transgenic line	HFD					+	+	++
	lSMS2-deficient knockout line	HFD					−	−	−
	Liver SMS2-overexpressing transgenic line	HFD			GW9662	Synthetic antagonist			−
Human			Huh7 hepatoma cells		Ceramide	Endogenous suppressor	−	−
Mouse	Wild type	CD		Fbw7 knockdown			+	+	++	[22]
	Wild type	CD		Fbw7/PPAR𝛾2 double knockdown			0/−	0/+	+
	Wild type	CD		Fbw7 transfected			−	−	0/−
Mouse	Wild type		Hepatocytes	Fbw7 knockdown			+	+	+
Mouse	Wild type	HFD					+	+	+	[23]
	Wild type	HFD, liquid, overfeeding					++	++	++
Mouse	Wild type	HFD					0/+	0/+	0/+	[24]
	Obese, hypercholesterolemic, diabetic foz/foz mice	CD					+	+	0/+
	Obese, hypercholesterolemic, diabetic foz/foz mice	HFD					+	++	+

Legend: Bold:  in vitro experiments; CD: control diet, HFD: high-fat diet; endpoints: empty cells: endpoint not determined, +: increase, −: decrease, 0: no effect, 1: controls taken for 100%; 0/+ and 0/− are used in cases where a clear-cut decision about the reported effects could not be done.