Mitigative effects of the bioactive flavonol fisetin on high‐fat/high‐sucrose induced nonalcoholic fatty liver disease in rats

Gaballah, Hanaa Hibishy; El‐Horany, Hemat El‐Sayed; Helal, Duaa S

doi:10.1002/jcb.28544

Cited by 22 publications

(13 citation statements)

References 62 publications

(113 reference statements)

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“…As aforementioned, fisetin is a flavonol compound that regulates lipid metabolism disorders, and anti-aging and anti-oxidation activities (30)(31)(32). A previous research has demonstrated that fisetin can inhibit the binding of ox-LDL to class B scavenger receptor cluster of differentiation 36 on macrophages and reduce foam cell formation to provide anti-AS effects (33).…”

Section: Discussionmentioning

confidence: 99%

Fisetin ameliorates atherosclerosis by regulating PCSK9 and LOX‑1 in apoE<sup>‑/‑</sup> mice

Jia

Cao

et al. 2020

Exp Ther Med

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The purpose of the current study was to investigate the mechanism by which fisetin improves atherosclerosis (AS) by regulating lipid metabolism and senescence in apolipoprotein E-deficient (apoE -/- ) mice. An AS model was established by feeding apoE -/- mice a high-fat diet. Mice were randomly divided into the model group (n=18), the fisetin group (n=18) and the atorvastatin group (n=18). The control group (n=18) was composed of wild-type C57BL/6 mice of the same age and genetic background. The fisetin and atorvastatin groups were respectively treated with aqueous solutions of fisetin (12.5 mg/kg) and atorvastatin (2 mg/kg) via oral gavage daily for 12 weeks. The pathological morphology, lipid accumulation, collagen deposition of the aortic sinus were observed, serum lipids, superoxide dismutase (SOD) and malondialdehyde (MDA) levels and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were measured in the peripheral blood serum. Additionally, the expressions of proprotein convertase subtilisin/kexin type 9 (PCSK9), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), tumor suppressor protein p53 (p53), cyclin-dependent kinase inhibitor 1A (p21) and multiple tumor suppressor-1 (p16) were analyzed in the aorta. The results of the current study indicated that compared with the control group, a large area of AS plaque in the aortic sinus that contained a large amount of red-stained lipids and decreased collagen fiber content were found in the model group, which exhibited higher total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), oxidized low-density lipoprotein (ox-LDL) and MDA levels; higher ALT and AST activities, lower high-density lipoprotein cholesterol (HDL-C) and SOD levels and increased expression levels of PCSK9, LOX-1, p53, p21 and p16. Fisetin is a phytochemical and bioflavonoid that serves a potential role in chronic diseases including AS, obesity, diabetes and cancer due to its wide biological activities, such as regulating lipid metabolism and anti-aging, anti-oxidation and anti-inflammatory. Atorvastatin is recognized as a first-line treatment drug for AS; therefore it was used as a positive control in the current study. Following fisetin and atorvastatin treatment, both the AS plaque and the lipid accumulation in the aortic sinus were significantly reduced, and the expressions of PCSK9, LOX-1 and aging markers, including p53, p21 and p16 were downregulated.

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Section: Discussionmentioning

confidence: 99%

Fisetin ameliorates atherosclerosis by regulating PCSK9 and LOX‑1 in apoE<sup>‑/‑</sup> mice

Jia

Cao

et al. 2020

Exp Ther Med

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“…Based on those findings, we studied human liver samples, and demonstrated a strong positive correlation between mRNA levels for HNF4α and SHBG, and found an inverse relationship with the amount of liver triglyceride ( 19 ). It is now known that HNF4α expression is reduced in rodents fed a high fat diet ( 20 ), and in liver samples from human patients with NASH ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

The hepatic lipidome and HNF4α and SHBG expression in human liver

Winters

Scoggins

Appiah

et al. 2020

Endocrine Connections

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Low plasma levels of sex hormone binding globulin (SHBG) are a marker for obesity, insulin resistance, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. The transcription factor HNF4α is a major determinant of hepatic SHBG expression and thereby serum SHBG levels, and mediates in part the association of low SHBG with hyperinsulinemia and hepatic steatosis. We analyzed the lipidome in human liver specimens from a cohort of patients who underwent hepatic resection as a treatment for cancer, providing insight into hepatic lipids in those without extreme obesity or the clinical diagnosis of NAFLD or non-alcoholic steatohepatitis. Both steatosis and high HOMA-IR were associated with higher levels of saturated and unsaturated FA, other than arachidonic, with the most dramatic rise in 18:1 oleate, consistent with increased stearoyl-Co A desaturase activity. Individuals with low HOMA-IR had low levels of total hepatic fatty acids while both low and high fatty acid levels characterized the high HOMA-IR group. Both insulin resistance and high levels of hepatic fat were associated with low expression levels of HNF4α and thereby SHBG, but expression of these genes was also low in the absence of these determinants, implying additional regulatory mechanisms that remain to be determined.

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“…For example, fisetin protected aging-induced rat brain degeneration by suppressing oxidative stress, inflammation, and apoptosis (Singh et al, 2018). Recently, fisetin was shown to impart beneficial effects in non-alcoholic fatty liver disease in male albino rats by the suppression of oxidative stress (Gaballah, El-Horany, & Helal, 2019). In mice, hepatic inflammation stimulated by a high fat-diet was blocked by fisetin (Xu et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

The plant flavonoid, fisetin alleviates cigarette smoke‐induced oxidative stress, and inflammation in Wistar rat lungs

et al. 2019

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In the present study, we tested the antioxidant and anti‐inflammatory potential of the plant flavonoid, fisetin against cigarette smoke‐induced oxidative stress, and inflammation in rat lungs. Male Wistar rats were chronically exposed to cigarette smoke (CS) with or without administration of fisetin. Fisetin administration to CS‐exposed rats resulted in a significant reduction in neutrophils and macrophages in bronchoalveolar lavage fluid as well as malondialdehyde, 3‐nitrotyrosine, 8‐isoprostane, tumor necrosis factor‐alpha, interleukin‐1beta, granulocyte macrophage‐colony stimulating factor, interleukin‐4, and interleukin‐10 levels in lung tissues compared to those in CS‐exposed rats not treated with fisetin. Fisetin also significantly augmented lung hemoxinase‐1, glutathione peroxidase‐2, reduced glutathione, superoxide dismutase, nitric oxide, and nuclear factor erythroid 2‐related factor (Nrf2) levels in CS‐exposed rats. In addition, a marked reversal in CS‐induced histopathological changes was noted in fisetin‐treated rats. Collectively, these data demonstrate the potential of fisetin to blunt CS‐induced oxidative stress and inflammation in the lung and to prevent tissue damage via the Nrf2‐mediated upregulation of antioxidant gene expression. Practical applications In the present study, we found that the plant flavonoid, fisetin significantly abrogated the oxidative stress, inflammation, and tissue damage induced by cigarette smoke, a powerful pro‐oxidant in rat lungs. Additionally, fisetin markedly reversed cigarette smoke‐induced increases in neutrophil and macrophage cell populations in bronchoalveolar lavage fluid. These findings are particularly significant considering the association of cigarette smoking with increased oxidative stress and inflammation, which are central to the pathologies of a wide variety of chronic diseases including chronic obstructive pulmonary disease, cancer, and cardiovascular diseases. Therefore, the present work underscores the beneficial effects of the regular consumption of plant‐based foods with medicinal properties for the effective prevention of these chronic diseases.

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Mitigative effects of the bioactive flavonol fisetin on high‐fat/high‐sucrose induced nonalcoholic fatty liver disease in rats

Cited by 22 publications

References 62 publications

Fisetin ameliorates atherosclerosis by regulating PCSK9 and LOX‑1 in apoE<sup>‑/‑</sup> mice

Fisetin ameliorates atherosclerosis by regulating PCSK9 and LOX‑1 in apoE<sup>‑/‑</sup> mice

The hepatic lipidome and HNF4α and SHBG expression in human liver

The plant flavonoid, fisetin alleviates cigarette smoke‐induced oxidative stress, and inflammation in Wistar rat lungs

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