TABLE 1.
Summary of available literature on possible mechanisms involved in therapeutic/preventive actions of naringenin on NAFLD-related conditions1
| Article type and type of study | Study, year (reference) | Samples | Study design | Main results |
|---|---|---|---|---|
| Obesity-related articles | ||||
| In vitro | Rebello et al., 2019 (40) | hADSC, pWAT | Administration of naringenin: 8 to 10 μM for 7–14 d | Increase in energy expenditure in hADSC; stimulation of expression of key enzymes involved in thermogenesis and insulin sensitivity in hADSC and pWAT; promotion of conversion of human white adipose tissue to a brown/beige phenotype |
| In vitro | Richard et al., 2013 (41) | Murine 3T3-L1 preadipocytes cultured in DMEM | Administration of naringenin: 22, 91, 183 μM for various times | Suppression of adipogenesis in a dose-dependent fashion as judged by examining lipid accumulation and induction of adipocyte marker protein expression; reduction of the ability of insulin to induce insulin receptor substrate 1 tyrosine phosphorylation and substantially inhibiting insulin-stimulated glucose uptake in a dose-dependent manner; prevention of adiponectin protein expression in mature murine 3T3-L1 adipocytes |
| In vitro | Yoshida et al., 2013 (42) | 3T3-L1 cells cultured in DMEM; RAW 264 cells cultured in DMEM | Administration of naringenin: 0, 1, 5, 10, 50, 100 μM for 3 h | Suppression of TLR2 expression during adipocyte differentiation via PPARγ activation; prevention of TNF-α–induced TLR2 expression by inhibiting the activation of NF-κB and JNK pathways; decrease in TLR2 expression in adipose tissue of HFD-fed mice; improvement in hyperglycemia and the suppression of inflammatory mediators, including TNF-α and MCP-1 |
| In vitro | Yoshida et al., 2010 (43) | 3T3-L1 cells maintained in DMEM | 3T3-L1 adipocytes were pretreated with hesperetin (100 μM) or naringenin (100 μM) for 30 min | An inhibition of TNF-α–stimulated FFA secretion from mouse adipocytes; blocking the TNF-α–induced activation of the NF-κB and ERK pathways; prevention of TNF-α from downregulating the transcription of 2 antilipolytic genes, including perilipin, and PDE3B via inhibition of the ERK pathway; and suppression of the transcription of IL-6 with naringenin treatment |
| In vitro | Hirai et al., 2007 (44) | RAW 264 macrophage cell line; 3T3-L1 preadipocytes | RAW 264 macrophage cell line, 3T3-L1 preadipocytes treated with 0, 25, 50, 100, 200 μM naringenin chalcone, naringenin, and rutin for 24 h | Prevention of the production of TNF-α, MCP-1, and NO by LPS-stimulating RAW 264 macrophages in a dose-dependent manner; exhibiting anti-inflammatory properties by inhibition of the production of proinflammatory cytokines in the interaction between adipocytes and macrophages by naringenin |
| In vitro | Harmon et al., 2003 (45) | 3T3-L1 preadipocytes cultured in DMEM | Administration of naringenin: 25, 50, 100 μM for 3 d | Inhibition of insulin-stimulated glucose uptake in 3T3-L1 adipocytes in a dose-dependent manner; exacerbating insulin resistance in susceptible individuals via impaired glucose uptake in adipose tissue |
| Animal | Tsuhako et al., 2019 (33) | Male C57BL/6J STD-fed mice, HFD (60% of calories from fat)-fed mice; 3T3-L1 cells; RAW 264 cells | HFD-fed mice treated with naringenin (100 mg/kg/d for 14 d); cell line and the co-culture system treated with naringenin or vehicle control were 0.6 mL and 1.0 mL, respectively | Suppression of macrophage infiltration into adipose tissue by inhibiting MCP-1 expression in the progression phase to HFD-induced obesity; inhibition of the HFD-induced expression of several chemokines, including MCP-1 and MCP-3, in adipose tissue; suppression of MCP-3 expression in 3T3-L1 adipocytes and a co-culture of 3T3-L1 adipocytes and RAW 264 macrophages |
| Animal | Burke et al., 2019 (34) | Lean, Ldlr-/- mice fed a nonpurified diet | Purified naringenin was continuously supplemented to the purified rodent chow by weight (3%; wt/wt) fed ad libitum for 8 wk | Reduction in body weight and adiposity; decrease in plasma lipids and increase in insulin sensitivity; elevation in energy expenditure |
| Animal | Burke et al., 2018 (35) | Ldlr-/- mice fed a nonpurified diet, HFHC (42% of calories from fat, 0.02% cholesterol)-fed mice, HFHC-fed mice supplemented with naringenin, HFHC-fed mice supplemented with nobiletin, HFHC-fed mice switched to nonpurified diet | HFHC diet–fed mice supplemented with 3% naringenin and 0.3% nobiletin for 12 wk | Prevention of obesity and adipocyte size and number through enhancing energy expenditure and increase in hepatic fatty acid oxidation; improvement in hyperlipidemia, insulin sensitivity, and hepatic steatosis with administration of naringenin |
| Animal | Ke et al., 2017 (36) | Semi-purified HFD (45% calories from fat)–fed mice; murine E0771 mammary tumor cell line | Male mice fed an HFD with 1% wt/wt and 3% wt/wt naringenin for 2 wk | Decrease in body weight, adipose mass, adipocyte size, α-SMA mRNA in mammary adipose tissue, and mRNA of inflammatory cytokines in both mammary and perigonadal adipose tissues |
| Animal | Ke et al., 2016 (37) | Female C57BL/6J mice fed a semi-purified HFD (45% of calories from fat) | Mice fed an HFD with 1% and 3% naringenin for 11 wk | Suppression of weight gain, reduction in hyperglycemia, and decrease in intra-abdominal adiposity; decrease in mRNA level for genes involved in de novo lipogenesis, lipolysis, and TG synthesis/storage |
| Animal | Assini et al., 2015 (23) | C57BL/6J wild-type mice and Fgf21-/- mice fed a standard nonpurified diet, HFD (42% kcal fat, 43% kcal carbohydrate, 0.05% cholesterol)-fed mice, HFD-fed mice supplemented with naringenin, low-fat semisynthetic diet supplemented with naringenin | Mice fed an HFD supplemented with 3% (wt/wt) naringenin, mice fed a low-fat semisynthetic diet supplemented with 3% (wt/wt) naringenin for 16 wk | Prevention of obesity; improving hepatic TG concentrations and normalizing hepatic expression of PGC1α, CPT1a, and SREBF1c; improvement in metabolic parameters |
| Animal | Ke et al., 2015 (38) | Ovariectomized C57BL/6J female mice fed a control diet | Standard diet supplemented with 3% wt/wt naringenin for 11 wk | Decrease in fasting glucose and insulin concentrations with >50% reduction in intra-abdominal and subcutaneous adiposity; decrease in plasma leptin and leptin mRNA in adipose depots; lowering hepatic lipid accumulation with corresponding alterations of hepatic gene expression associated with de novo lipogenesis, fatty acid oxidation, and gluconeogenesis |
| Animal | Yoshida et al., 2014 (39) | Male C57BL/6J STD-fed mice, HFD (60% of calories from fat)-fed mice treated with vehicle control, HFD-fed mice treated with naringenin; 3T3-L1 cells and RAW 264 cells | HFD-fed mice treated with naringenin (100 mg/kg/d) for 1, 7, or 14 d | Suppression of macrophage infiltration into adipose tissue; not demonstrating any differences in HFD-induced changes of serum biochemical parameters; prevention of MCP-1 in adipose tissue via preventing JNK pathway; suppression of MCP-1 expression in adipocytes, macrophages, and a co-culture of adipocytes and macrophages |
| Animal | Cho et al., 2011 (24) | Male Long-Evans hooded rats fed a commercial nonpurified diet | Semipurified, powdered diets were prepared for concentrations of naringenin: 0%, 0.003%, 0.006%, and 0.012% of diet for 6 wk | Reduction in the amount of total TG and cholesterol in plasma and liver; decrease in adiposity and TG contents in parametrial adipose tissue; increase in PPARα protein expression in the liver; enhancement of expression of CPT-1 and UCP2 |
| Liver-related articles | ||||
| In vitro | Goldwasser et al., 2010 (62) | Huh7 cells cultured in DMEM | Administration of naringenin: 0–500 μM for 24 h | Regulation of nuclear receptors PPARα, PPARγ, and LXRα activity; activation of the ligand-binding domain of both PPARα and PPARγ, while inhibition of LXRα in GAL4-fusion reporters; inducing the expression of PGC1α; induction of PPAR-regulated fatty acid oxidation genes such as CYP4A11, ACOX, UCP1 and ApoAI, and inhibition of LXRα-regulated lipogenesis genes, such as FAS, ABCA1, ABCG1, and HMGR; decrease in cholesterol and bile acid production |
| In vitro | Allister et al., 2008 (63) | HepG2 cells cultured in DMEM | HepG2 cells grown in 6-well culture dishes were incubated with either insulin (25 nM or 100 nM), naringenin (25 μM or 100 μM), or the combination of insulin and naringenin at various concentrations up to 60 min | Induction of signaling required the insulin receptor and sensitized the cell to the effects of insulin; upregulation of the LDL receptor, downregulation of microsomal TG transfer protein expression, and inhibition of apoB-100 secretion via activation of both PI3-K and MAPKerk signaling |
| Animal | Ahmed et al., 2019 (46) | STD-fed male Wistar rats | Administration of naringenin: 20 mg/kg by oral gavage for 4 wk | Reduction of the elevated serum AST, ALT, ALP, LDH, and GGT activities as well as total bilirubin and TNF-α concentrations; reduction in the elevated liver lipid peroxidation and enhancement of the liver glutathione content and SOD, GST, and GPx activities; downregulating the elevated hepatic proapoptotic mediator protein 53, Bax, and caspase-3 and upregulating the suppressed antiapoptotic protein Bcl-2 |
| Animal | Rashmi et al., 2018 (61) | Streptozocin-treated male albino mice, liver tissue fixed in 10% buffered formalin | Oral administration of 50–100 mg/kg naringenin for 45 d | Neutralizing 1) hydroxyl radicals, 2) superoxide, 3) hydrogen peroxide, 4) NO radicals, 5) DPPH, and 6) lipid peroxidation; reduction in lipid peroxidation and increase in antioxidant concentrations |
| Animal | Zhao et al., 2018 (47) | STD-fed male ICR mice received CMC-Na, STD-fed mice received alcohol, STD-fed mice received different flavonoids | Mice were supplied orally with 5 kinds of different flavonoids (naringenin, apigenin, quercetin, epigallocatechin gallate, genistein) at an equimolar concentration of 81 mg/kg for each group for 5 wk | Reduction in fibrosis and apoptosis in the liver; attenuation of lipid deposition, partial inflammatory-related factors (NF-κB, COX-2, and IL-6 concentrations), and hepatic histopathological alterations; improvement in serum biochemistry markers, hepatic lipid accumulation, lipid peroxidation, antioxidant capacities, and inflammation by naringenin treatment |
| Animal | Chen et al., 2017 (48) | Male C57BL/6 mice fed STD, mice fed methionine choline–deficient diet | Administration of naringenin: 25, 50, 100 mg/kg for 1 wk; administration of nano-naringenin: 25 mg/kg for 1 wk | Inhibition of the serum ALT and AST concentrations; decrease in lipid accumulation in the mice livers |
| Animal | Wang et al., 2016 (49) | Male specific pathogen-free BALB/c mice fed a standard diet; liver tissue | Administration of naringenin: 50 or 100 mg/kg for 14 d | Decrease in serum concentrations of ALT and AST, liver index, hepatic malondialdehyde content, and increase in hepatic glutathione content and SOD activity; antiapoptotic effects via a connection with the regulation of Bax and Bcl-2 protein expression in hepatic tissue |
| Animal | Sirovina et al., 2016 (50) | Swiss albino inbred mice fed a standard laboratory diet | Naringenin ethanolic solution (0.5% vol/vol) was given to mice intraperitoneally (50 mg/kg/d) for 7 d | Reduction in lipid peroxidation in liver and kidney tissue; decrease in number of vacuolated liver cells and degree of vacuolization |
| Animal | Ozkaya et al., 2016 (51) | Wistar albino male rats divided in 4 groups: control, naringenin, lead acetate, lead acetate + naringenin; liver tissue | Naringenin (50 mg/kg, dissolved in corn oil) was administered by the orogastric gavage during 30 d with intervals of 1 d | Decrease in the grade of necrosis, hydropic degeneration, and hepatic cord disorganization |
| Animal | Chtourou et al., 2015 (52) | Male Wistar rats divided in 4 groups: control, STD-fed mice supplemented with naringenin, HCD (prepared by adding 10 g cholesterol/kg to STD)-fed mice, HCD-fed mice supplemented with naringenin, mice received normal pellet and treated with naringenin | Administration of naringenin: 50 mg/kg for 90 d | A decrease in the plasma fatty acid composition, the hepatic proinflammatory mediators, and the expression of relevant genes including TNF-α, IL-6, IL-1β, iNOS, and MMP-2, 9; reduction in macrophage infiltration, and inhibition of oxidative stress–related biomarker concentrations |
| Animal | Motawi et al., 2014 (54) | Female Wistar rats fed a standard nonpurified diet divided in 4 groups: control, simvastatin, naringenin, simvastatin + naringenin | Administration of naringenin: 20–50 mg/kg/d for 4 wk; administration of simvastatin: 20–40 mg/kg/d for 4 wk | An improvement in liver function, oxidative stress, protein profile, DNA fragmentation, and the histopathological changes by administration of naringenin |
| Animal | Mershiba et al., 2013 (55) | Male rats divided into 4 groups: control, arsenic, naringenin, arsenic + naringenin | Administration of naringenin: 20–50 mg/kg/d for 28 d | Restoring the activities of serum biomarkers and antioxidant enzymes in the tissues in a dose-dependent manner |
| Animal | Jayaraman et al., 2012 (30) | Male Wistar rats fed standard diet divided in 4 groups: groups 1 and 2 received isocaloric glucose, groups 3 and 4 received 20% ethanol, groups 2 and 4 received naringenin | Administration of naringenin: 50 mg/kg/d for 30 d | Decrease in the concentrations/activities/expressions of serum AST, ALT, iron, ferritin, TNF-α, IL-6, NF-κB, COX-2, MIP-2, CD14, and iNOS protein adducts in the liver |
| Animal | Jain et al., 2011 (56) | Male Wistar rats fed standard diet divided into 2 groups: control, received arsenic | Administration of naringenin: 50 mg/kg, orally once daily for 2 wk; administration of silymarine: 50 mg/kg, orally once daily for 2 wk | An increase in glutathione concentrations; improvement in the recovery of altered SOD and CAT activity by naringenin treatment |
| Animal | Jayaraman and Namasivayam, 2011 (57) | Male albino rats fed standard pellet diet divided into 4 groups: groups 1 and 2 received isocaloric glucose, groups 3 and 4 received 20% ethanol, groups 2 and 4 received naringenin | Administration of naringenin: 50 mg/kg for 30 d | A decrease in the levels/activities of bilirubin, ALP, LDH, TBARS, LOOH, CD, and phase I enzymes, and elevation in the activities of ADH, SOD, CAT, and phase II enzymes |
| Animal | Kannappan et al., 2010 (58) | Male Wistar rats received standard pellet diet and water ad libitum divided into 4 groups: control, high-fructose diet (60% fructose, 20% casein)–fed mice, HFD-fed mice supplemented with naringenin, received naringenin | Administration of naringenin: 50 mg/kg/d for 45 d | Inhibition of liver cell leakage, lipid peroxidation, and protein oxidation; improvement in enzymatic antioxidant status; improvement in nonenzymatic antioxidant concentrations |
| Animal | Renugadevi and Prabu, 2010 (59) | Male Wistar rats received commercial standard pelleted diet divided into 5 groups: control, normal naringenin, cadmium, cadmium in combination with naringenin | Administration of naringenin: 25 or 50 mg/kg/d for 4 wk | Reversing the activities of serum hepatic marker enzymes to their near-normal concentrations; reduction in lipid peroxidation and restoring the concentrations of antioxidant defense in the liver |
| Animal | Pari and Gnanasoundari, 2006 (60) | Male Wistar rats fed a pellet diet divided into 5 groups: control, naringenin, oxytetracycline, naringenin, and oxytetracycline | Administration of naringenin: 25 or 50 mg/kg orally for 15 d | Decrease in activities of serum AST, ALT, ALP, and LDH and the concentrations of bilirubin along with reduction in the concentrations of lipid peroxidation markers in the liver; increase in the activities of SOD, CAT, and glutathione peroxidase as well as the concentrations of glutathione, vitamin C, and vitamin E in liver |
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ABCA1, ATP binding cassette transporter A-1; ABCG1, ATP binding cassette subfamily G member 1; ACOX, peroxisomal acyl-coenzyme A oxidase; ADH, alcohol dehydrogenase; ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; Bax, Bcl-2-associated protein; Bcl-2, B-cell lymphoma 2; CAT, catalase; CD, conjugated dienes; CMC-Na, carboxymethyl cellulose solution; COX, cyclooxygenase; CPT-1, carnitine palmitoyltransferase 1; CYP4A11, cytochrome P450 family 4 subfamilies A member 1; DPPH, diphenyl picrylhydrazyl; ERK, extracellular signal–regulated kinase; FAS, fatty acid synthase; FFA, free fatty acid; Fgf21, fibroblast growth factor 21; GGT, γ-glutamyl transferase; GPx, glutathione peroxidase; hADSC, human white adipocyte cultures; HCD, high-cholesterol diet; HFD, high-fat diet; HFHC, high-fat cholesterol–containing; HMGR, HMG-CoA reductase; iNOS, inducible NO synthase; JNK, Jun N-terminal kinase; LDH, lactate dehydrogenase; LOOH, lipid hydroperoxides; LXRα, liver X-receptor α; LXRE, LXRα response element; MAPKerk, mitogen-activated protein kinase/extracellular-regulated kinase; MCP, monocyte chemoattractant protein; MIP-2, macrophage inflammatory protein 2; MMP, matrix metalloproteinase; NAFLD, nonalcoholic fatty liver disease; PDE3B, phosphodiesterase 3B; PGC1α, peroxisome proliferator-activated receptor γ coactivator 1α; PI3-K, phosphoinositide-3-kinase; PPAR, peroxisome proliferator-activated receptors; pWAT, subcutaneous abdominal adipose tissue; SOD, superoxide dismutase; SREBF1c, sterol regulatory element-binding transcription factor 1c; STD, standard diet; TBARS, thiobarbituric acid reactive substances; TG, triglyceride; TLR2, Toll-like receptor 2; UCP, uncoupling protein; α-SMA, α-smooth muscle actin.