Polyphenols are potent antioxidants, capable of neutralizing free radicals that cause oxidative stress. Oxidative stress is linked to the development of chronic diseases like cancer, diabetes, and cardiovascular diseases. For instance, the high antioxidant activity of polyphenols like catechins in green tea, cardamom and resveratrol in red wine is thought to contribute to their protective effects against these diseases (54–57).

Chronic inflammation is implicated in numerous health issues, including heart disease, arthritis, and neurodegenerative conditions. Polyphenols such as curcumin (from turmeric) and anthocyanins have been shown to suppress pro-inflammatory markers, thus potentially reducing the risk of inflammatory diseases (58, 59).

Polyphenols have been extensively researched for their cardiovascular benefits. For example, the flavonoids in dark chocolate and the resveratrol in red wine have been linked to improved endothelial function, reduced blood pressure, and a decreased risk of atherosclerosis. These effects are primarily attributed to their antioxidant and anti-inflammatory properties (60, 61).

Several studies suggest that polyphenols, such as curcumin, resveratrol, and ellagic acid, may have anticancer properties. They can modulate various molecular pathways involved in cancer cell proliferation, apoptosis (programmed cell death), and metastasis. For example, resveratrol has been shown to inhibit cancer cell growth in vitro and in animal models, particularly in breast and colon cancer (60, 62).

Emerging evidence suggests that polyphenols may play a protective role in brain health. Flavonoids, such as those found in berries, are thought to improve cognitive function and protect against age-related cognitive decline. Resveratrol and epigallocatechin gallate (EGCG) have also been shown to have potential in preventing neurodegenerative diseases like Alzheimer’s and Parkinson’s by reducing oxidative stress and inflammation in the brain (63, 64).

Curcumin (CUR) is one of the most studied polyphenols in this field (all studies are summarized in Table 2). There are some in vitro studies which have confirmed the impact of CUR on SREBP expression. One of the first studies was conducted by Kang and Chen which examined CUR on hepatic satellite cells and observed that CUR decreased the levels of LDL receptors (LDLR) in these cells, leading to a reduction in cellular cholesterol levels. This effect was possible through regulating the levels of SREBP. However, they declared that CUR affects this transcriptional factor through the activation of PPARγ (90). Yuan et al. (91) gathered 23 apoE−/− mice and categorized them into three groups: control (n = 7), curcumin-treated (n = 8), and Lovastatin-treated (n = 8). They fed these mice with 20 mg/kg/day for 4 months and examined Intracellular lipid level, Serum lipid and lipoprotein, and atherosclerotic lesions in these mice. Eventually, they observed that curcumin is able to decrease the size of atherosclerotic plaques, stabilize them, decrease TC, TG, and LDL-C serum levels, while increasing HDL, and decrease cholesterol accumulation. It seems that one of the mechanisms by which CUR exerts all these effects is through inhibiting high fat-induced e SREBP-1 expression in apoE−/− mice and inhibiting the SREBP-1/caveolin-1 pathway (91). Immunofluorescence examinations also showed that curcumin treatment is able to inhibit the translocation of SREBP-1 from the cytoplasm into the nucleus (91). There are plenty of other in vivo studies that has observed the same results. For instance, according to a study, 100 mg/kg/day of curcumin for 8 weeks can significantly reduce both plasma and renal triglyceride levels in humans (92). Moreover, in diabetic rats treated with curcumin, there was an increase in AMPK phosphorylation. This treatment also inhibited the elevated renal expression of SREBP-1c, leading to a reduction in the levels of acetyl CoA carboxylase, fatty acid synthase, and adipose differentiation-related protein, which is an indicator of cytoplasmic droplets. These findings showed that curcumin helps prevent the progression of diabetic nephropathy via the AMPK–SREBP pathway (92). However, there are also some paradoxical results. A study shows that curcumin’s effects on SREBP expression are not directly exerted (93). In this study, Caco-2 cells were gathered to examine the dynamics of precursor and mature SREBP-2, SP-1, and SCAP in relation to dosage and timing. Following treatment with curcumin, researchers observed the distribution of SREBP-2 within the cells and assessed the expression of the S1P protein. Curcumin was found to lower the mRNA levels of SREBP2, SP-1, and SCAP, but it did not reduce the expression levels of precursor SREBP-2 (pSREBP-2) and SCAP at the same time. Additionally, curcumin appears to hinder the proteolytic processing of SREBP-2, leading to decreased production of the mature SREBP-2 (mSREBP-2) and altering the cellular distribution of SREBP-2 (93). The inhibitory impact of curcumin on SP-1 protein levels is temporary. While curcumin can decrease the mRNA and protein levels of S1P, it does not significantly affect the mRNA and protein levels of S2P (site-2 protease). Additionally, curcumin inhibits the proteolytic process of SREBP-2, leading to a reduction in mSREBP-2, which acts as a transcription factor that regulates genes involved in cholesterol metabolism. However, curcumin does not directly inhibit the expression of the mSREBP-2 protein (93). A similar study also indicated that CUR decreases the gene expression of SP-1 and lowers its trans-activation function, a process facilitated by the activation of PPARγ. Chromatin immuno-precipitation analysis confirms curcumin’s inhibitory impact on SP-1’s binding to the GC-box. In conclusion, their findings show that curcumin inhibits srebp-2 expression in cultured HSCs by activating PPARγ and diminishing SP-1 activity, which results in the downregulation of ldlr expression (94) (Figure 2).

There the combination of CUR with aerobic training is able to reduce insulin resistance, lower serum insulin levels, decrease the ratio of low-density lipoprotein to high-density lipoprotein, and reduce the total cholesterol to high-density lipoprotein ratio, while increasing serum high-density lipoprotein cholesterol (95).

Quercetin is also another member of the flavonoid family which is effective on regulating the expression of SREBPs in vivo and in vitro (96). Quercetin notably enhanced the expression of SR-BI in HepG2 cells in a way that depended on both concentration and time. Additionally, quercetin stimulated the binding of 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (Dil)-labeled HDL to liver cells and the uptake of 125I/3H-CE-HDL. However, using small interfering RNA (siRNA) or the specific SR-BI inhibitor, BLT-1, blocked the binding of Dil-HDL and the selective uptake of HDL-C induced by quercetin (96) (Figure 3).

Other than these common polyphenols, some other members of this family are also examined on hepatic cells for a better understanding of their effects on lipid metabolism. For instance, Baicalein which is a flavonoid extracted from Scutellaria baicalensis is administered on HepG2 cells by Jiang et al. (97). They detected that in HepG2 cells with oleic acid and palmitic acid-induced lipid accumulation, the administration of baicalein decreases the levels of TG, total cholesterol, and lipid droplets mainly through regulating SREBP1. This flavonoid lowers the levels of type 1 SREBP as well as lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1) indirectly through pregnane X receptor (PXR) pathway (97).

Luteolin is another flavonoid with the chemical formula of C15H10O6 which is extracted from Reseda luteola. A study tried to explore the capabilities of luteolin as a modulator of lipid metabolism (98). They observed that this agent is able to regulate lipid metabolism through the inhibition of SREBP-1c expression. However, they declared that this effect is indirect and luteolin affects this transcriptional factor by the means of inhibiting LXRα/β transcriptional activity (98). The results of another study on luteolin indicate that a week of dietary supplementation with this natural compound led to the increased expression of PPAR-α and its target gene, carnitine palmitoyl transferase 1 (CPT-1), in the livers of rats. luteolin-7-glucoside (L7G) also appeared to reduce the liver levels of SREBP-1, but it did not influence the protein levels of fatty acid synthase (FAS). While the mRNA levels of SREBP-2 and LDL receptor (LDLr) remained unchanged, the expression of HMGCR was diminished (99). Other studies on these polyphenols as well as some other ones including resveratrol are summarized in Table 2.

There are only a limited number of studies which investigate the effect of resveratrol and exercise on SREBP.

Jeong et al. (100) are one of the research groups which worked in this field and aimed to compare the effects of moderate exercise training versus resveratrol supplementation, both combined with a low-fat diet, on lipid metabolism in the skeletal muscle of mice with obesity induced by a high-fat diet. Thirty male C57BL/6J mice (5 weeks old) were fed a high-fat diet (45% fat) for 8 weeks to induce obesity. Subsequently, all mice switched to a low-fat diet during an 8 weeks intervention phase, where they were divided into three groups: low-fat diet control (HLC), low-fat diet with resveratrol supplementation (HLR), and low-fat diet with exercise (HLE). The HLE group performed treadmill running (30–60 min/day at 10–22 m/min, 0% incline, 5 days/week), while the HLR group received resveratrol (10 mg/kg body weight) by gavage, 5 days/week (100). They detected that mice in the HLE group showed a significant reduction in body weight, as well as decreased expression of the lipogenesis marker SREBP and the inflammatory cytokine TNF-α in skeletal muscle. In contrast, resveratrol supplementation with a low-fat diet did not produce significant changes in these parameters. Moderate aerobic exercise combined with a low-fat diet is more effective than resveratrol supplementation in improving lipid metabolism and reducing inflammation in the skeletal muscle of high-fat diet-induced obese mice (100).

Another study also aimed to compare the effectiveness of resveratrol supplementation versus aerobic exercise training, both combined with a low-fat diet, on adipogenesis and inflammation-related markers in adipose tissue of high-fat diet-induced obese mice (101). They used fifteen male C57BL/6 mice (4 weeks old) were initially fed a high-fat diet (45% fat) for 12 weeks to induce obesity, followed by a low-fat diet (10% fat) for 8 weeks. The mice were divided into three groups (n = 5 each): low-fat diet control (HLC), low-fat diet plus resveratrol supplementation (HLR), and low-fat diet plus aerobic exercise (HLE). The HLE group underwent treadmill running for 30–60 min per day at 10–22 m/min, 0% incline, five times per week for 8 weeks. At the end of the 20 weeks protocol, epididymal fat pads were collected for analysis (101).

The HLE group exhibited significantly lower body weight and adipose tissue mass compared to the HLC group. Fatty acid synthase (FAS) expression was significantly reduced in both HLR and HLE groups compared to HLC, while acetyl-CoA carboxylase (ACC) expression was significantly decreased only in the HLE group. Tumor necrosis factor-alpha (TNF-α) expression was significantly reduced in both HLR and HLE groups, and monocyte chemoattractant protein-1 expression was significantly lowered in the HLE group. Taken together, both resveratrol supplementation and aerobic exercise, when combined with a low-fat diet, improved adipogenesis and inflammatory markers in adipose tissue compared to diet alone. However, aerobic exercise appeared to be more effective in reducing obesity-induced metabolic dysfunction (101).

Bergamot (Citrus bergamia Risso et Poiteau) is a small, citrus fruit primarily cultivated in the Calabria region of southern Italy. It is renowned for its essential oil, which has widespread applications in the pharmaceutical, cosmetic, and food industries. Bergamot oil is a key ingredient in Earl Gray tea and is valued for its distinctive aroma and potential therapeutic properties. Bergamot is rich in polyphenolic compounds, including flavonoids such as naringin, neoeriocitrin, neohesperidin, brutieridin, and melitidin (102). These compounds are responsible for its strong antioxidant and anti-inflammatory properties. Notably, brutieridin and melitidin exhibit statin-like activity, potentially contributing to lipid regulation through inhibition of HMG-CoA reductase (102, 103).

Bergamot flavonoids help lower lipid levels through several key mechanisms that affect lipid metabolism. They activate sirtuin-1 and AMPK-α—important regulators of cellular energy balance—which boost the breakdown of fatty acids by stimulating CPT1. At the same time, they suppress the production of very-low-density lipoprotein (VLDL) by inhibiting HNF4 and SREBP-1, two proteins involved in lipid synthesis (104). Additionally, bergamot flavonoids enhance the activity of LDL receptors in two ways: by increasing the expression of these receptors via PKC activation, and by promoting their movement to the cell surface through PPAR-γ activation. These combined effects lead to a notable decrease in LDL cholesterol and shift LDL particles from smaller, more harmful types to larger, less dangerous ones—ultimately improving the overall lipid profile (105).

Notwithstanding the beneficial effects of bergamot in regulating lipid metabolism, the studies investigating the effects of this agent on the expression of hepatic transcription factors is limited. A recent study in 2022 has investigated the health benefits of dietary fibers (DFs) extracted from bergamot, focusing on weight loss and cholesterol-lowering effects, along with the underlying biological mechanisms (106). In a 6 weeks feeding trial on Sprague-Dawley rats, bergamot DFs showed dose-dependent protective effects against metabolic syndrome. They helped reduce body weight gain, BMI, and Lee’s index without suppressing appetite. Bergamot DFs also significantly lowered triglycerides (TG), total cholesterol (TC), LDL-C, and atherogenic index (AI) in rats fed a high-fat diet and improved liver pathology. Exploring the underlying mechanisms of these effects shows that bergamot is able to decrease the expression of SREBP-1c and SREBP-2 in hepatic tissues (106).

In another study, the effect of bergamot PF extract on 2D and 3D hepatocyte cultures was also examined (107). In this study, different liver cell models were treated with bergamot PF extract to evaluate its effects under various conditions. In the 2D culture model, McA Rh-7777 rat hepatoma cells were treated for 24 h with 50 μM oleic acid conjugated to fatty acid-free bovine serum albumin (BSA) to induce lipid accumulation. Alongside oleic acid, the cells were exposed to bergamot PF extract dissolved in the culture medium at concentrations of 0.001, 0.01, 0.1, and 1 μg/mL (107). For the 3D spheroid model, composed of HepG2 and LX-2 cells, treatment began 24 h after cell seeding. These spheroids were exposed to bergamot PF extract at a concentration of 1 μg/mL for a total of 72 h, with the treatment medium being refreshed every 48 h to maintain consistent exposure. Similarly, primary human liver organoids, formed from cryopreserved hepatocytes, were treated with 1 μg/mL bergamot PF extract starting 24 h after seeding. The treatment continued for 6 days, with half of the medium replaced every 48 h to ensure the presence of fresh extract throughout the duration of the experiment (107). This integrated treatment approach across different liver models allowed for a comprehensive assessment of bergamot PF extract’s potential metabolic effects. Their results show that in McA Rh7777, following a 24 h incubation period, a dose-dependent rise in Srebp-1c levels was noted (p = 0.01). in 3D HEPG2/LX2 Spheroids, after a 96 h incubation, they found that the bergamot PF extract had no effect on the expression levels of SREBP-1C (107).

Curcumin is one of the polyphenols which is able to alter the expression of PPARs. An in vitro study in 2009 shows that CUR is able to decrease the levels of LDLR in activated hepatic satellite cells, leading to a reduction in cellular cholesterol levels. The activation of peroxisome proliferator-activated receptor-γ (PPARγ) by curcumin influenced the expression of transcription factors known as sterol regulatory element-binding proteins (SREBPs) in activated hepatic stellate cells (HSCs), ultimately suppressing the expression of the LDLR gene. A recent study attempted to show the effectiveness of fermented Curcuma longa L. in the development of alcoholic fatty liver in mice and explored the mechanisms involved. They detected that C. longa. pretreatment notably reduced the increased accumulation of hepatic lipid droplets caused by ethanol consumption. When compared to the ethanol-treated control group, mice that underwent FT pretreatment displayed a decrease in the production of cytochrome P4502E1 (CYP2E1), SREBP-1c, and acetyl-CoA carboxylase. On the other hand, they had higher levels of AMP-activated protein kinase, PPAR-α, and carnitine palmitoyltransferase 1 (CPT-1). Overall, CUR shows great potential as a liver protectant in preventing alcoholic fatty liver by influencing the processes of fatty acid production and breakdown; however, further studies need to be done to ensure long-term efficacy and safety of this agent (108).

For a better understanding of the effects of CUR on the cholesterol efflux process of adipocytes, Dong et al. (109) used Rabbit subcutaneous adipocytes and treated these cells with 5, 10, and 20 μg/ml curcumin. They assessed the levels of PPARγ mRNA in these cells after CUR treatment and found out that CUR has the ability to enhance cholesterol efflux from adipocytes by the means of increasing the expression of PPARγ in a dose-dependent manner. They confirmed these results by pre-treating these cells with GW9662 (a potent and selective PPARγ antagonist), and observed that the increased expression of PPARγ (after CUR treatment) is partially prevented (109).

Quercetin is also another flavonoid which is approved to enhance conditions associated with metabolic syndrome, specifically issues like excess body weight, abnormal lipid levels, and glucose intolerance (110). In an in vivo study, quercetin was orally administered (10 g quercetin/kg food in a high-sucrose diet) to rats and morphometric and metabolic factors, as well as the transcriptomic profiles of the liver and retroperitoneal fat of these rats were evaluated afterward. The relative weights of epididymal and retroperitoneal fat were notably reduced in the animals treated with quercetin. Additionally, the PD-Q rats showed a smaller area under the glycemic curve and a lower fasting insulin level (110). Although there were no alterations in total cholesterol levels, the overall triglyceride levels decreased in both the serum and liver of the PD-Q rats. The transcriptomic analysis of the liver and adipose tissue supported the metabolic and structural observations, showing a pattern aligned with insulin-sensitizing changes, with key regulatory factors identified as PPARγ, Adipoq, Nos2, and Mir378 (110). Other studies on these polyphenols as well as some other ones including resveratrol are summarized in Table 3.

The number of studies in this field are very restricted. Bergamot PF extract has shown promising effects in combating liver steatosis, although the precise mechanisms responsible for these benefits are not yet fully understood. In one study, we investigated the impact of bergamot PF extract on both 2D and 3D hepatocyte culture models, including rat cells, human hepatoma cells, and primary human hepatocytes (107). Their results demonstrated that, in 2D cultures, treatment with bergamot PF significantly reduced intracellular lipid accumulation. This reduction was accompanied by increased expression of genes involved in fatty acid β-oxidation—specifically Acox1, Pparα, and Ucp2—as well as genes associated with lipophagy, such as Atg7. These lipid-lowering effects were further confirmed in more physiologically relevant 3D models, including hepatic spheroids and liver organoids. Overall, their findings suggest that bergamot PF extract reduces intracellular lipid storage, likely by enhancing metabolic pathways related to β-oxidation and lipid degradation, highlighting its potential therapeutic value in managing liver steatosis (107).

Another study tried bergamot on Sprague-Dawley (SD) rats for 6 weeks and found that in addition to controlling weight, bergamot DFs significantly lowered TG, TC, LDL-C, and the AI, all of which were elevated due to a high-fat diet. Liver histological analysis confirmed improvements in fat-related liver damage. At the molecular level, Western blot analysis revealed that bergamot DFs enhanced the expression of liver proteins involved in cholesterol breakdown, such as LXRα and CYP7A1, while reducing the expression of lipogenic proteins including SREBP-1c, FAS, ACC, and SREBP-2. Furthermore, gene expression analysis via qRT-PCR showed that the DFs upregulated key thermogenic and metabolic regulators—PGC-1α, PRDM16, UCP-1, and PPARγ—in brown adipose tissue, indicating enhanced energy expenditure (107).

The study also found that bergamot DFs helped normalize the gut microbiota composition disrupted by a high-fat diet. Among the different fiber types tested, soluble dietary fiber (SDF) and total dietary fiber (TDF) proved more effective in promoting weight loss and lowering lipid levels than insoluble dietary fiber (IDF) at equivalent doses. In conclusion, bergamot-derived dietary fibers exhibited strong potential to reduce body weight and blood lipid levels by modulating lipid metabolism, stimulating thermogenesis, and improving gut health. These findings support their potential use in developing functional foods aimed at preventing or managing obesity and hyperlipidemia (107).

Yan et al. (111) are one of the research groups which tried to examine the effects of curcumin on these transcriptional factors. They examined the impact of curcumin on the interplay between the metabolism of endogenous bile acids and the metabolism of external xenobiotics in C57BL/6 mice with NAFLD caused by a high-fat and high-fructose diet (HFHFr) (111). Their findings show that curcumin treatment significantly reduced hepatic steatosis and normalized serum biochemical parameters in mice on a high-fat-high-fructose diet. Curcumin successfully adjusted the expression levels of CYP3A and CYP7A in the fatty liver condition, thereby restoring metabolic function. Additionally, curcumin regulated lipid synthesis, as shown by the changes in the expressions of CD36, SREBP-1c, and FAS. Moreover, there was a notable decrease in the expressions of FXR, SHP, and Nrf2 in the HFHFr-fed mice (111). They also observed that Prior treatment with the LXRα antagonist GGPP reduced the impact of curcumin on CYP3A, CYP7A, and SREBP-1c (111). In an ex vivo study, Dong et al. (109) tried to explain the underlying mechanisms by which CUR is able to increase cholesterol efflux from adipocytes. They used RT-PCR for detecting the altered gene expression caused by CUR in these cells and found out that LXR is one of the main genes which is up-regulated as a result of CUR treatment (109). A similar study also used CUR on THP-1 Macrophage-Derived Foam Cells to assess the same effects (112). They observed that CUR significantly enhanced the expression of ATP-binding cassette transporter 1 (ABCA1), facilitated the removal of cholesterol from foam cells derived from THP-1 macrophages, and lowered cholesterol levels within cells. It also stimulated AMP-activated protein kinase (AMPK) and SIRT1, which subsequently activated LXRα in these foam cells (112). Blocking AMPK/SIRT1 activity with a specific inhibitor or small interfering RNA may prevent LXRα activation and eliminate the curcumin-induced expression of ABCA1 and cholesterol efflux. Consequently, curcumin promoted cholesterol efflux by increasing ABCA1 expression via the activation of the AMPK-SIRT1-LXRα signaling pathway in foam cells derived from THP-1 macrophages (112). Peschel et al. (113) tried CUR on HepG2 cells and found out that this method leads to a concentration-dependent increase of up to seven times in LDL-receptor mRNA levels. In contrast, the mRNAs for the genes responsible for the sterol biosynthetic enzymes HMG CoA reductase and farnesyl diphosphate synthase show only a slight increase at high curcumin concentrations, which also results in reduced cell viability (113).

In another point of view, CUR is also effective for enhancing cognitive function in mice which have developed dementia as a result of lipid metabolic disorder (114). In this regard, CUR enhanced the unique cognitive and memory functions in transgenic mice with Alzheimer’s Disease. In these mice, the total serum cholesterol levels decreased with a curcumin-rich diet, while high-density lipoprotein levels increased. This dietary intake of curcumin was linked to lower levels of Aβ and higher levels of liver X receptor-β, ATP-binding cassette A1, and apolipoprotein A1 in the CA1 region of the hippocampus (114). In the brains of Alzheimer’s Disease mice that were given a curcumin diet, the levels of mRNA and protein for retinoid X receptor-α, liver X receptor-β, and ATP binding cassette A1 were increased (114).

Quercetin is also another polyphenol which has some effects on the expression levels of these transcriptional factors. In vitro studies has shown that quercetin is able to increase the expression of LXR in hepatic cells and this effect can be reverted by the administration of LXR siRNA (96). Other than LXR, quercetin is also able to impact RXR. According to a study by Jiang et al. (97) which cultured human adipocytes either in a state where they are actively producing and gathering more lipids through lipogenesis (“active lipogenic state”) or in a state where they are keeping their stored lipids stable without any increase (“lipid storage state”); it is reported that In the “lipid storage state,” a prolonged treatment involving three doses over 72 h with low levels of quercetin and ferulic acid together led to a significant reduction in stored lipid levels, changes in lipid composition, and modulation of genes associated with lipid metabolism. This suggests a notable involvement of PPARα and RXRα (115). However, In the “continuous lipogenic state,” the impacts of quercetin and ferulic acid differ significantly, showing minimal alterations in gene expression and lipid makeup. Additionally, there is no identifiable role of PPARα/RXRα, and a concentration ten times greater is needed to reduce stored lipid levels (115). Plus, Quercetin, even at concentrations of up to 30 μM, did not harm differentiated THP-1 cells. It enhanced the messenger RNA and protein levels of ABCA1 in these cells, with the most significant effects observed at 0.3 μM after 4–8 h of incubation. Additionally, quercetin raised the protein levels of PPARγ and LXRα within just 2 h of treatment. Since PPARγ and LXRα play crucial roles as transcription factors for ABCA1, the increase in ABCA1 caused by quercetin may be mediated through these factors (116).

Resveratrol is also an important polyphenol which is effective on LXR and FXR either administered alone or in combination with exercise. A study evaluated the therapeutic effects of resveratrol, exercise training, and their combination on hepatic function and gene expression in rats with NAFLD (117). The animals were randomly assigned to seven groups, including controls and interventions involving resveratrol, interval or continuous exercise, and their combinations. The control group exhibited significantly higher mRNA expression levels of LXR, FXR, and SIRT1 compared to all other experimental groups (p < 0.001) (117). Additionally, both the resveratrol-treated and exercise-trained groups demonstrated elevated expression of these genes relative to the patient and saline groups (p < 0.01). Notably, the combined treatment of resveratrol and exercise training resulted in a markedly greater increase in the mRNA expression of FXR, LXR, and SIRT1 compared to either intervention alone (p < 0.001) (117). Their results demonstrated that both resveratrol and exercise independently enhanced the expression of Sirt1, Lxr, and Fxr, while also reducing markers of liver injury and apoptosis. However, the combined intervention of resveratrol with either interval or continuous exercise yielded significantly greater improvements across all parameters. These findings suggest a synergistic effect between resveratrol and physical activity, offering a promising combined approach for managing NAFLD through improved liver function and regulation of transcriptional pathways involved in lipid metabolism (117).

Similarly, another study also investigated the effects of resveratrol on SIRT1 and other genes related to lipid metabolism (118). In this study, 28 male rats (weighing 260 ± 10 g, 8 weeks old) were randomly assigned to four groups (n = 8 per group): control (C), aerobic training (T), supplement (S), and combined training with supplement (T-R). The training groups underwent aerobic exercise on a treadmill for 14 weeks (five sessions per week, 45 min per session) (118). Tissue protein levels of UCP-1, SIRT1, and PGC-1α were measured using ELISA. Data were analyzed using ANOVA, with statistical significance set at p ≤ 0.05. Significant increases in SIRT1 and PGC-1α were observed in the liver and subcutaneous/visceral adipose tissues, respectively (P ≤ 0.05 and P ≤ 0.001). UCP-1 levels were significantly higher in the group receiving both resveratrol supplementation and aerobic training (P ≤ 0.001) (118). The findings suggest that combining resveratrol supplementation with aerobic exercise produces greater effects on increasing UCP-1, SIRT1, and PGC-1α protein expression than either intervention alone, potentially improving liver function and promoting the conversion of subcutaneous white adipose tissue to a beige or intermediate phenotype (118).

In another study, 32 male mice (average weight 16 ± 4 g) were randomly assigned to four groups (n = 8): Control, resveratrol, Aerobic Exercise (Exe), and Resveratrol combined with Aerobic Exercise (resveratrol + Exe) (119). Mice in the resveratrol and resveratrol + Exe groups received resveratrol via gavage five times per week for 8 weeks. The Exe and resveratrol + Exe groups underwent treadmill training at 50%–65% of VO₂max, five sessions per week for 8 weeks. They observed that resveratrol alone increased FNDC5, SIRT1, and UCP1 gene expression compared to the control group (119). Aerobic exercise alone significantly upregulated all five genes compared to control. Notably, the combined resveratrol + Exe group showed significantly higher expression of all thermogenic and browning-related genes compared to either intervention alone. Additionally, the resveratrol + Exe group exhibited improved lipid profiles, with higher HDL and lower LDL, triglycerides, and total cholesterol (119).

Zahedi et al. (120) also identified that resveratrol supplementation combined with aerobic exercise likely exerts a stronger effect on increasing SIRT1 and PGC-1α expression in the soleus muscle and inguinal adipose tissue, as well as UCP-1 expression in inguinal adipose tissue, compared to either intervention alone. This combined approach appears to be more effective than resveratrol or physical activity alone in promoting the browning of subcutaneous white adipose tissue, potentially inducing a shift toward a beige or intermediate adipocyte phenotype (120).

There is also one paradoxical study in this field that aimed to evaluate the effects of aerobic exercise and resveratrol supplementation on mitochondrial biogenesis in the skeletal muscle of mice with obesity induced by a high-fat diet (121). Forty male C57BL/6 mice (4 weeks old) were randomly assigned to four groups (n = 10 per group): normal diet (NC), high-fat diet (HC), high-fat diet with resveratrol supplementation (HRe), and high-fat diet with aerobic exercise (HE) (121). The aerobic exercise regimen involved treadmill running for 40–60 min per day at a speed of 10–14 m/min, 0% incline, 4 days per week for 16 weeks. Resveratrol was administered orally at a dose of 25 mg/kg body weight, four times per week for the same duration.

Results showed a significant reduction in COX-IV mRNA expression in the HC group compared to the NC group (p < 0.05), indicating a negative impact of the high-fat diet. However, the HE group exhibited significantly increased expression of SIRT3, PGC-1α, and COX-IV mRNA in skeletal muscle compared to both the HC and HRe groups (p < 0.05) (121). In conclusion, high-fat diet-induced obesity suppressed mitochondrial biogenesis gene expression in skeletal muscle, while aerobic exercise effectively restored and enhanced it. Resveratrol supplementation alone did not significantly influence mitochondrial biogenesis, suggesting that aerobic exercise is the more effective intervention for improving mitochondrial function in obese skeletal muscle (121).

Other than these polyphenols, Baicalein which is a flavonoid derived from Scutellaria baicalensis is also examined on HepG2 cells (97). According to this study, this polyphenol is able to enable the movement of pregnane X receptor (PXR) into the nucleus and regulate the expression of its target genes. In HepG2 cells that experienced lipid buildup due to oleic acid and palmitic acid, treatment with baicalein decreased the levels of triglycerides, total cholesterol, and lipid droplets (97). The findings from the computer simulation showed that baicalein acts as a natural ligand for PXR (97). Luetolin is also another important member of the flavonoid family which has the ability to affect LXRα/β (98). An in vitro study examined the expression levels of LXR-target genes using real-time RT-PCR. Specifically, they looked at sterol regulatory element binding protein 1c (SREBP-1c) in liver cells and ATP-binding cassette transporter (ABC)A1 in macrophages. The lipid levels in liver cells were assessed through Oil Red staining (98). The findings of this revealed, for the first time, that luteolin effectively blocked the transcriptional activity induced by LXRα/β agonists. As a result, it inhibited SREBP-1c expression, reduced lipid accumulation, and affected ABCA1 expression. Thus, luteolin has the potential to counteract hypertriglyceridemia linked to LXR activation, suggesting possible therapeutic benefits for related conditions (98). Other studies on these polyphenols as well as some other ones including resveratrol are summarized in Table 4.