Quercetin Treatment Ameliorates Inflammation and Fibrosis in Mice with Nonalcoholic Steatohepatitis3

Abstract

We investigated whether quercetin protects from steatosis and limits the expression of proinflammatory and fibrogenic genes in C57BL/6J mice with nonalcoholic steatohepatitis (NASH) induced by feeding a methionine-choline-deficient (MCD) diet. Quercetin (50 mg/kg) was given by oral route daily. Mice were randomly divided into 4 groups that received for 2 or 4 wk: the control diet plus vehicle, control diet plus quercetin, MCD diet plus vehicle, and MCD diet plus quercetin. At both 2 and 4 wk, feeding the MCD diet resulted in liver steatosis, inflammatory cell accumulation, oxidative stress evaluated by the concentration of TBARS, and fibrosis evidenced by the staining of α-smooth muscle actin-positive cells in the liver. At both 2 and 4 wk, the MCD diet induced an increase in the mRNA levels of Il6, Tnf, Ptgs2, and Hmgb1 and increased the protein concentrations of Toll-like receptor-4, c-Jun terminal kinase, and p65 NFκB subunit compared with control rats. Feeding the mice the MCD diet also triggered an increase of Col1a1, Col3a1, Plod3, Tgfb1, Smad3, Smad7, Pdgfb, Ctgf, Areg, Mmp9, and Timp1 mRNA levels. These effects were totally or partially prevented by treatment with quercetin. The data obtained suggest that attenuation of multiple profibrotic and proinflammatory gene pathways contributes to the beneficial effects of quercetin in mice with MCD diet-induced steatohepatitis.

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

“…These findings were associated with a marked inhibition of HFD-induced TLR-4 expression at transcriptional level and the modulation of TLR-4-NF-B signaling pathway activation by quercetin, and a downregulation of TNF- and IL-6 gene expression, confirming its well-known anti-inflammatory capacity [5,26,59,60]. TNF- and IL-6 play a key role in glucose homeostasis impairment associated with HFD [61], suggesting that proinflammatory cytokines blockage by quercetin contributes to its anti-insulin resistance properties.…”

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

“…TGF-b signals stimulate through transmembrane receptors cytoplasmic Smad proteins, which in turn modulate the transcription of target genes, including those encoding ECM components. 2 In the context of liver fibrosis, Smad3 is pathogenic because mice null for Smad3 are protected against dimethylnitrosamine-induced hepatic fibrosis. 31 Our data demonstrate that the upregulation of TGF-b was associated with increased phosphorylation of Smad3, effects which were partially abrogated by melatonin.…”

“…40 We have previously reported that suppression of amphiregulin signals contributes to the protective effects of quercetin in cirrhotic rats with common bile duct ligation, 7 and in mice fed a methionine-choline-deficient diet. 2 It is also known that amphiregulin amplifies the HSC response through increased production of CTGF and TIMP-1. 39 Thus, the inhibition of amphiregulin expression by melatonin in CCl 4 -treated mice supports the suggestion that suppression of the amphiregulin signaling system could be a new target in the prevention of liver fibrosis.…”

“…Other cytokines, such as plateletderived growth factor (PDGF) or connective tissue growth factor (CTGF), and the epidermal growth factor receptor amphiregulin, play an important fibrogenic role. 2 Moreover, fibrogenesis is a dynamic process involving not only net accumulation of ECM but also its ongoing remodeling by proteases, including the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs). 3 Recent clinical and experimental evidence indicates that hepatic fibrosis may be reversed on removal of the underlying etiologic agent.…”

Hepatoprotective Effect of Quercetin Pretreatment Against Paracetamol-Induced Liver Damage and Partial Hepatectomy in Rats

“…In addition, since the development of fibrosis in liver is progressive and dependent on the activation of hepatic stellate cells, intervals of 24h and 72h are too short to allow observation of significant production of collagen fibers. Other studies with different models of carbon tetrachloride-induced toxic hepatitis 9,18 or a model of methionine-choline deficient diet 19 or studies of arsenite-induced lesions 15 describe attenuation of fibrosis by quercetin. Kawada et al 20 showed that quercetin and other natural phenolics inhibit stellate cell activation by disturbing signal transduction pathways and cell protein expression, thus interrupting the differentiation of stellate cells into myofibroblasts, and the consequent production of collagen type I and II.…”