Effects of resveratrol and other polyphenols in hepatic steatosis

Table 1 In vitro studies performed with polyphenols

Ref.	Animal model	Polyphenol dose and treatment period length	Effects	Mechanisms
Gnoni et al[27], 2009	HepG2 cells	25 μmol/L resveratrol	↓ Triacylglycerols	↓ ACC activity = FAS activity
		30 min
Zang et al[29], 2006	HepG2 cells	10 μmol/L resveratrol	Prevent lipid accumulation	↑ phosphorylation AMPK (activation) in liver
		24 h		↑ phosphorylation ACC (inhibition) in liver
Shang et al[30], 2008	HepG2 cells	50 μmol/L resveratrol	↓ Triacylglycerols	↑ phosphorylation AMPK liver (activation)
		24 h		↓ mRNA de SREBP1c and FAS liver
Wang et al[28], 2009	Human HepG2 cells	40 μmol/L resveratrol	↓ Triacylglycerols	↓ SREBP 1c
		24 h		↑ SIRT 1
Vidyashankar et al[53], 2013	Hep G2 cells	10 μmol/L quercetin	↓ Triacylglycerols
		24 h	↓ Insuline resistance
			↓ Oxidative stress
			↑ Superoxide dismutase, catalase and glutathione peroxidase activities
Guo et al[60], 2011	Hep G2 cells	Anthocyanin Cy-3-g	↓ Triacylglycerols	Inhibit translocation of GPAT1
		1, 10, 100 μmol/L		↓ GPAT, mtGPAT1 activity
		24 h
Baselga-Escudero et al[61], 2012	FAO cells	Proanthocyanidins	↓ MiR-122 at 25,50,	25 mg/L, ↓ FAS (5 h) protein expression
		10, 25, 50, 100 mg/L	100 mg/L
		1 h	↓ MiR.122, FAS with time (1, 3 h. 25 mg/L)
Pil Hwang et al[62], 2013	Hep G2 cells	3-caffeoyl, 4-dihydrocaffeoylquinic acid	↓ Fat accumulation in a dose-dependent manner	↓ SREBP1c, FAS mRNA and protein expression = LXRα mRNA expression
		1, 3, 10 μmol/L
		1 h		↑ Activating AMPK
				↑ SIRT1
Liu et al[65], 2011	HepG2 cells	Blueberry extract	↓ Triacylglycerols accumulation
		20, 40, 60, 80 and 100 μg/mL 24 h	80 μg/m L ↓ 60% of triacylglycerols accumulation
Lee et al[67], 2012	BALB/c normal liver cells	Extract of Hibicus sabdariffa L	↑ Cell viability	↓ p-JNK and AIF, tBid and Bax protein expression
	Steatosis produced by	0.05, 0.1, 0.5, 1 mg/mL		↓ Lipid peroxidation
	acetaminophen	48 h		↑ Catalase and GSH
Wang et al[66], 2012	HepG2	Extract of Ginkgo biloba	↓ Triacylglycerols	↑ CPT-1a, ACO mRNA expression
		200 μg/mL in vitro		↓ FAS, Acac-β mRNA expression
		24 h		↑ CPT-1a protein expression

↓: Decrease; ↑: Increase. RSV: Resveratrol; ACC: Acetyl CoA carboxylase; FAS: Fatty acid synthase; AMPK: AMP-activated kinase; SREBP1c: Sterol regulatory element binding protein 1c; SIRT1: Sirtuin 1; Q: Quercetin; GPAT1: Glycerol-sn-3-phosphate acyltransferase 1; mtGPAT1: Mitochondrial glycerol-sn-3-phosphate acyltransferase 1; LXRα: Liver X receptor α; pJNK: Activated c-Jun N-terminal kinase; AIF: Apoptosis inducing factor; GSH: Glutathione; CPT-1a: Carnitine palmitoyltransferase 1a; ACO: Acyl-coenzyme A oxidase 1; Acacβ: Acetyl-coenzyme A carboxylase β.

Table 2 In vivo studies carried out with resveratrol

Ref.	Animal model	Resveratrol dose and treatment period length	Effects	Mechanisms
Baur et al[31], 2006	Male C57BL/6NIA mice fed a high-fat diet	0.04% in the diet (estimated 22.4 mg/kg bw per day)	↓ Lipid droplets in liver	↓ Acetylation status of PGC-1α protein in liver
		6 wk
		186 mg kg bw per day	↑ Mitochondrial number
		6 wk
Kasdallah-Grissa et al[39], 2006	Male Wistar rats fed a standard diet	0.04% in the diet (estimated 300-450 mg/kg bw per day)	↓ Oxidative stress
	3 g ethanol/kg bw per day	6 wk	↓ Lipid peroxidation
Ahn et al[32], 2008	Male C57BL6/J mice fed an atherogenic diet	0.0125% in the diet (estimated 10 mg/kg bw per day)	↓Total lipids and triacylglycerols in liver	↓ Expression lipogenic enzymes
		8 wk	Ameliorated necroinflammation	↑ Expression enzymes involved in fatty acid oxidation
				↑ SIRT1 mRNA expression
Ajmo et al[40], 2008	Male C57BL/6J mice fed a low-fat diet	200 mg/kg bw per day	↓ Liver weight	↓ SREBP-1c mRNA and protein expressions
	Ethanol added to account 29% of total calories	400 mg/kg bw per day 4 wk	↓ Lipid droplets	↓ FAS, SCD, ACC, ME mRNA
			↓ Triacylglycerols	↑ PGC-1α mRNA
				↑ ACO, CPT-1a mRNA
				↑ Fatty acid oxidation
				Activation AMPK/SIRT1 axis
Bujanda et al[37], 2008	Male Wistar rats	10 mg/kg bw per day	↓ Liver fat infiltration
	Steatosis induced by feeding rats ad libitum for four days per week and then fasting them the remaining three days	4 wk	↓ Oxidative stress ↓ ALT
Kim et al[33], 2008	C57BL/6J mice a high fat diet	0.4% in the diet (estimated 400 mg/kg bw per day) 10 wk	↓ Liver weight
			↓ Triacylglycerols
Shang et al[30], 2008	Male Wistar rats fed a high-fat, high-sucrose diet	100 mg/kg bw per day 10 wk	↓ Triacylglycerols	↑ AMPK phosphorylation (activation)
			↓ Lipid droplets	↓ SREBP-1c and FAS mRNA
Rivera et al[42], 2009	Male fa/fa Zucker rats fed standard diet	10 mg/kg bw per day 8 wk	↓ Triacylglycerols	↓ ACC activity
				AMPK activation
Cho et al[34], 2012	Male C57BL/6J mice fed a high-fat diet	0.005% in the diet (0.5 mg/kg bw per day)	0.5 mg/kg bw per day	↓ PAP = Enzymes involved in fatty acid oxidation
		10 wk	↓ Triacylglycerols
			↓ Number and size of liver fat droplets	↓ FAS and ME activities
		0.02% in the diet (2 mg/kg bw per day)	2 mg/kg bw per day ↓ Triacylglycerols	↓ PAP = Enzymes involved in fatty acid oxidation
		10 wk	↓ Number and size of liver fat droplets
Gómez-Zorita et al[43], 2012	Male fa/fa Zucker rats fed a standard diet	15 mg/kg bw per day	15 and 45 mg/kg bw	= Lipogenic enzyme activity
		45 mg/kg bw per day	↓ Liver weight	↑ Activity of enzymes involved in fatty acid oxidation
			↓ Triacylglycerols
		6 wk	↓ Oxidative stress
			15 mg/kg bw↓ Transaminases
Poulsen et al[35], 2012	Male Wistar rats fed a high-fat diet	100 mg/kg bw per day	Normalized triacylglycerols No hepatic inflammation	↑ UCP2 ↑ Mitochondria number
		8 wk
Alberdi et al[36], 2013	Male Sprague-Dawley rats fed a high-fat, high-sucrose diet	30 mg/kg of bw per day	↓ Triacylglycerols	↑ Activity of enzymes involved in fatty acid oxidation = FAS, G6PDH, ME activities
		6 wk
				↑ Phosphorylated ACC/total ACC (inhibition)
				↑ Phosphorylated AMPK/total AMPK (activation)
				= PPAR-α, SREBP-1c, SIRT1, PGC-1α, TFAM, COX2, and HNF-4α, ↓ Acetylated PGC-1α /total PGC-1α (activation)
Franco et al[38], 2013	Lactating Wistar rats	30 mg/kg per day	↓ Triacylglycerols
		4 wk	↓ Oxidative stress

↓: Decrease; ↑: Increase. BW: Body weight; PGC-1α: Peroxisome proliferator-activated receptor-c coactivator 1 α; SIRT1: Sirtuin 1; SREBP-1c: Sterol regulatory element binding protein 1c; FAS: Fatty acid synthase; SCD: Stearoylcoenzyme A desaturase; ACC: Acetyl CoA carboxylase; ME: Malic enzyme; ACO: Acyl-coenzyme A oxidase 1; CPT-1a: Carnitine palmitoyltransferase 1a; AMPK: AMP-activated kinase; ALT: Alanine aminotransferase; PPAR-γ: Peroxisome proliferator-activated receptor γ; C/EBP: CCAAT/enhancer binding protein; LXR: Liver X receptor; PAP: Phosphatidate phosphohydrolase; UCP2: Mitochondrial uncoupling protein 2; G6PDH: Glucose-6-phosphate dehydrogenase; PPAR-α: Peroxisome proliferator-activated receptor α; TFAM: Mitochondrial transcription factor A; COX2: Cyclooxygenase 2; HNF-4 α: Hepatocyte nuclear factor 4 α.

Table 3 In vivo studies carried out with quercetin

Ref.	Animal model	Quercetin dose and treatment period length	Effects	Mechanisms
Kobori et al[55], 2009	BALB/c mice with STZ-induced diabetes and steatosis fed a standard diet	0.5% in the diet	↓ Oxidative stress
		2 wk	↓ Liver damage
Kobori et al[56], 2011	C57BL/6 J mice fed a high-fat diet	0.5% in the diet	↓ Triacylglycerols	Normalized gene expression of PPAR-γ, SREBP-1c, FAS, CD36
		20 wk	↓ Oxidative stress	↑ PPAR-α mRNA expression
Marcolin et al[58,59], 2012, 2013	Male C57BL/6J mice fed a diet deficient in methionine and choline	0.005% in the diet	↓ Macro/micro vesicular steatosis	↓ Proinflammatory ond profibritic gene expression
		4 wk	↓ Balloning
			↓ Serum transaminases
			↓ Oxidative stress
			↓ DNA damage
Panchal et al[57], 2012	Male Wistar rats fed a high-fat diet	0.8% in the diet (50 mg/kg bw per day)	Attenuated steatosis	↑ Nrf2
		8 wk		↓ NF-kβ
				↑ CPT-1a
Jung et al[50], 2013	C57B1/6 mice fed a high-fat diet	0.025% in the diet	↓ Liver weight	↓ FAS, Acaca, Apoa4, Abcg5, Fdft1 and GPAM mRNA expressions
			↓ Triacylglycerols
		8 wk	↓ Lipid droplet size
Ying et al[54], 2013	Gerbils fed a high-fat diet	15, 30, 60 mg/kg bw per day	All doses
			↓ Triacylglycerols
		2 wk	↓ Lipid droplets size
			↓ Serum transaminases
			60 mg/kg bw per day
			↓ Liver collagen

↓: Decrease; ↑: Increase. STZ: Streptozotocin; PPAR-γ: Peroxisome proliferator activated receptor γ; SREBP-1c: Sterol regulatory element binding protein 1c; FAS: Fatty acid synthase; CD36: Cluster of differentiation 36; PPAR-α: Peroxisome proliferator activated receptor α; BW: Body weight; CPT-1a: Carnitine palmitoyltransferase 1a; Acaca: Acetyl-coenzyme A carboxylase α; Apoa4: Apolipoprotein A-IV; Abcg: ATP-binding cassette, subfamily G, member 5; Fdft1: Farnesyl-diphosphate farnesyltransferase 1; Gpam: Glycerol-3-phosphate acyltransferase, mitochondrial.

Table 4 In vivo studies carried out with other polyphenols

Ref.	Animal model	Polyphenols dose and treatment period length	Effects	Mechanisms
Guo et al[60], 2011	Male KKAy mice fed a standard diet	Anthocyanin Cy-3-g	↓ Triacylglycerols	↓ GPAT1 activity
		0.01% in the diet	↓ Lipid droplets
		12 wk
Baselga-Escudero et al[61], 2012	Male Wistar rats fed a standard diet and 2.5 mL of lard oil/kg BW	Proanthocyanidins	↓ Triacylglycerols	↓ FAS mRNA
		250 mg/kg BW		↑ miR-122 mRNA
		3 h
Luo et al[64], 2012	Male C57BL/6 mice fed a methionine and choline-deficient high-fat diet	Theaflavin	↓ Cell ballooning
		30 mg/kg BW	↓ Microvesicular and
		by intraperitoneal injection	macrovesicular
		48, 24, and 2 h before induction of steatosis by ischemia-reperfusion	steatosis
			↓ ALT
			↓ Oxidative stress
			↓ Hepatocyte apoptosis
			↓ F4/80-positive cells (inflammatory cells)
Yoshimura et al[63], 2013	KKAy mice fed a high-fat diet	Ellagic acid	↓ Serum ALT, AST,	↑ FAS mRNA expression = Acaca, SREBP-1c mRNA expression
		0.1% in the diet	↓ Macrovesicular steatosis
		68 d	↓Triacylglycerols	= ACO mRNA expression
				↑ CTP-1a, PPAR-α mRNA expression

↓: Decrease; ↑: Increase. GPAT1: Glycerol-sn-3-phosphate acyltransferase 1; BW: Body weight; FAS: Fatty acid synthase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Acaca: Acetyl-CoA carboxylase α; SREBP-1c: Sterol regulatory element binding protein 1c; ACO: Acyl-coenzyme A oxidase; CPT-1a: Carnitine palmitoyltransferase 1a; PPAR-α: Peroxisome proliferator activated receptor α.

Table 5 In vivo studies carried out with polyphenol extracts

Ref.	Animal model	Polyphenols extract, dose and treatment period length	Effects	Mechanisms
Feillet-Coudray et al[72], 2009	Male Wistar rats fed a high-fat diet	Provinol®, a polyphenol extract obtained from red wine	↓ Macroesteatosis
		0.2% in the diet	↓ Lipid droplets
		6 wk	↓ Lipid peroxidation
Aoun et al[73], 2010	Male Wistar rats fed a high fat diet	Provinol®, a polyphenol extract obtained from red wine	↓ Triacylglycerols	↑ SIRT protein expression
		0.2% in the diet	↓ Macroesteatosis
		6 wk	= Fatty acid composition	= SCD1, pAMPK, SREBP-1c, FAS, HNF-4 α, PGC1α and CPT-1a protein expression
Beltrán-Debón et al[68], 2011	LDLr-/- mice fed a standard diet	Aspalathus linearis L. (rooibos)	Lower steatosis degree	↑ AMPK protein expression
		10 g/L drinking water
		14 wk
Tsuruta et al[69], 2011	db/db mice fed a standard diet	Nelumbo nucifera L. (lotus root)	↓ 15% Liver weight (tendency)	= CPT-1a activity
		0.5% in the diet	↓ 62%Triacylglycerols (tendency)	↓ FAS, ME activity
		3 wk	↓ Transaminases (tendency)
Axling et al[70], 2012	C57BL/6 J mice fed a high fat diet	Green tea	↓ Liver weight	↓ SREBP-1c, PPAR-γ, ACC mRNA (22 wk)
		4% in the diet	↓ Triacylglycerols
		11 and 22 wk	↓ Serum ALT
Lee et al[67], 2012	BABL/c mice fed a standard diet Steatosis produced by acetaminophen	Extract of Hibicus sabdariffa L 0.01%, 0.02% or 0.03% in the diet 2 wk	↓ Liver damage ↓ Liver steatosis ↓ Serum ALT, AST (dose dependent) ↓ Oxidative stress	↓ p-JNK and AIF, tBid and Bax protein expression
Wang et al[66], 2012	Male Wistar rats fed a high-fat diet	Extract of Ginkgo biloba	↓ Triacylglycerols	↑ CPT-1a activity
		0.25% in the diet		↑ CPT-1a, Acaa1, Slc25a20, Hadh, ACO, PPAR-α, RXR-α mRNA expression,
		12 wk		↓ FAS mRNA expression
Park et al[71], 2013	C57BL/6 J mice fed a high-fat diet	Extract of grape skin	↓ Triacylglycerols	↓ FAS, SCD1, PAP
		0.15% in the diet	↓ Serum leptin	↑CPT-1a, PPAR-α mRNA expressions and activities
		(160 mg/kg bw per day)	↑ Serum adiponectin	↓ PPAR-γ,
		10 wk		↑ PPAR-α, CPT-1a mRNA expressions
				↑β oxidation,
				= CPT-1a activity
Yui et al[74], 2013	OLETF rats fed a standard diet	Humulus lupulus L. (hop pomace)	↓Liver weight (tendency)	↓de novo lipogenesis
		1% in the diet	↓ Triacylglycerols (tendency)	= ACO, CPT-1a activity
		70 d

↓: Decrease; ↑: Increase. SIRT: Sirtuin 1; SCD1: Stearoyl-CoA desaturase; AMPK: AMP-activated kinase; pAMPK: Phosphorylated AMP-activated kinase; SREBP-1c: Sterol regulatory element binding protein 1c; FAS: Fatty acid synthase; HNF-4α: Hepatocyte nuclear factor 4 α; PGC-1α: Peroxisome proliferator-activated receptor-c coactivator 1α; CPT-1a: Carnitine palmitoyltransferase 1a; ME: Malic enzyme; ALT: Alanine aminotransferase; PPAR-γ: Peroxisome proliferator activated receptor γ; ACC: Acetyl CoA carboxylase; pACC: Phosphorylated acetyl CoA carboxylase; AST: Aspartate aminotransferase; p-JNK: Activated c-Jun N-terminal kinase; AIF: Apoptosis inducing factor; Acaa1: acetyl-coenzyme A acyltransferase 1; Slc25a20: Solute carrier family 25, member 20; Hadh: Hydroxyacyl-coenzyme A dehydrogenase; ACO: Acyl-coenzyme A oxidase; PPAR-α: Peroxisome proliferator activated receptor α; RXR-α: Retinoid X receptor α; PAP: Phosphatidate phosphohydrolase.