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

Abstract

Abbreviations: ALT, alanine aminotransferase; C/EBPα, CCAAT/enhancer binding protein alpha; CHOP, CCAAT-enhancer-binding protein homologous protein; CYP2E1, cytochrome P450 2E1; DAMPs, danger-associated molecular patterns; FABP1, fatty acid binding protein 1; FAS, fatty acid synthase; FAT/CD36, fatty acid translocase CD36; FFA, free fatty acid; FOXA1, forkhead box protein A1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GRP78, 78 kDa glucose-regulated protein; HFD, high fat diet; HOMA-IR, homeostasis model assessment of insulin resistance; IAP, intestinal phosphatase alkaline; IL-6, interleukin 6; LPO, lipid peroxidation; LPS, lipopolysaccharide; LXRα, liver X receptor alpha; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, non-alcoholic steatohepatitis; NF-B , nuclear factor kappa B; NLRP3, NOD-like receptor family pyrin domain containing 3;PAMPs, pathogen-associated molecular patterns; PRRs, pattern recognition receptors; SCFAs, short-chain fatty acids; SREBP-1c, sterol regulatory element binding protein 1c; TG, triglycerides; TLR, Toll-like receptor; TNF-αtumor necrosis factor; UPR, unfolded protein response. AbstractGut microbiota is involved in obesity, metabolic syndrome and the progression of nonalcoholic fatty liver disease (NAFLD). It has been recently suggested that the flavonoid quercetin may have the ability to modulate the intestinal microbiota composition, suggesting a prebiotic capacity which highlights a great therapeutic potential in NAFLD. The present study aims to investigate benefits of experimental treatment with quercetin on gut microbial balance and related gut-liver axis activation in a nutritional animal model of NAFLD associated to obesity. C57BL/6J mice were challenged with high fat diet (HFD) supplemented or not with quercetin for 16 weeks.

Mice Fed a High‐Cholesterol Diet Supplemented with Quercetin‐3‐Glucoside Show Attenuated Hyperlipidemia and Hyperinsulinemia Associated with Differential Regulation of PCSK9 and LDLR in their Liver and Pancreas

“…Some studies have shown that dietary quercetin can reduce diet‐induced obesity; others have not . Difference in diets as well as quercetin molecular forms, dosage, and duration of treatment could explain these discrepancies.…”

Quercetin reduces atherosclerotic lesions by altering the gut microbiota and reducing atherogenic lipid metabolites

“…This correlation is supported by a preclinical study in which the administration of a quercetin supplement reduced the progression of atherosclerosis (Shen et al ). In addition, studies of animals fed high‐fat diets (HFD) supplemented with quercetin reported reduced body weight gains (Kobori et al ; Porras et al ) and lipid deposition in the liver and white adipose tissues (WAT) (Panchal et al ; Kim et al ). Studies of humans and mice also showed that quercetin treatment reduced the plasma triglyceride concentration, another risk factor associated with CVD (Sahebkar ; Dai et al ).…”

SIRT3 Deficiency Promotes High‐Fat Diet‐Induced Nonalcoholic Fatty Liver Disease in Correlation with Impaired Intestinal Permeability through Gut Microbial Dysbiosis

“…Furthermore, CB2 is currently considered a promising anti‐inflammatory and antifibrogenic target for NAFLD . It has been implied that one crucial factor in the development of NAFLD is metabolic endotoxemia . CD14 is an accessory receptor for the Toll‐like receptor‐4 (TLR4)‐mediated recognition of LPS .…”