Nobiletin Ameliorates Nonalcoholic Fatty Liver Disease by Regulating Gut Microbiota and Myristoleic Acid Metabolism

Abstract

Disturbance of the gut microbiota plays a critical role in the development of nonalcoholic fatty liver disease (NAFLD). Increasing evidence supports that natural products may serve as prebiotics to regulate the gut microbiota in the treatment of NAFLD. In the present study, the effect of nobiletin, a naturally occurring polymethoxyflavone, on NAFLD was evaluated, and metabolomics, 16S rRNA gene sequencing, and transcriptomics analysis were performed to determine the underlying mechanism of nobiletin, and the key bacteria and metabolites screened were confirmed by in vivo experiment. Nobiletin treatment could significantly reduce lipid accumulation in high-fat/high-sucrose diet-fed mice. 16S rRNA analysis demonstrated that nobiletin could reverse the dysbiosis of gut microbiota in NAFLD mice and nobiletin could regulate myristoleic acid metabolism, as revealed by untargeted metabolomics analysis. Treatment with the bacteria Allobaculum stercoricanis, Lactobacillus casei, or the metabolite myristoleic acid displayed a protective effect on liver lipid accumulation under metabolic stress. These results indicated that nobiletin might target gut microbiota and myristoleic acid metabolism to ameliorate NAFLD.

Heptamethoxyflavone Alleviates Metabolic Syndrome in High-Fat Diet-Fed Mice by Regulating the Composition, Function, and Metabolism of Gut Microbiota

“…Gut dysbiosis was linked to obesity and obesity-related metabolic diseases in humans . An increasing number of experimental and clinical studies have proved that the modulation of gut microbiota is a novel strategy in preventive and therapeutic approaches for MS-related diseases. , To date, several studies have demonstrated that gut microbiota was a potential target for PMFs to ameliorate NAFLD, diabetes, and other MS-related diseases. ,, Among these, Zeng et al confirmed that PMF-rich extracts attenuated MS by targeting and restoring gut microbiota through fecal microbiota transplant and antibiotic treatment experiments . Here, we found that HMF obviously changed the gut microbiota composition at the genus and species levels in HFD-fed mice.…”

“…Moreover, it has been reported that gut microbiota interacts with the host by means of metabolites . Gut microbiota-derived metabolites, particularly bile acids and short-chain fatty acids (SCFAs), have been demonstrated to play a pivotal role in regulating the host’s glucose and lipid metabolism and inflammation. , Many phytochemicals have been demonstrated to prevent and treat MS-related diseases by modulating gut microbiota and microbial metabolites. − Li et al found that theabrownin inhibited obesity and NAFLD via modulating the serotonin level and the composition and metabolic function of gut microbiota . Thus, the modulation of gut microbiota and its relevant metabolites might be a novel treatment target for MS-related diseases .…”

“…Therefore, most of orally administered HMF would enter into the colon and potentially influence gut microbiota. Additionally, several recent in vivo studies have reported that the effects of PMFs on alleviation of MS-related diseases were largely mediated by gut microbiota and the production of microbial metabolites. ,, Thus, it spurred us to investigate whether HMF-mediated alleviation of MS was associated with the regulation of gut microbiota and fecal metabolites. Here, we conducted integrative fecal metagenomic and metabolomic analyses to elucidate the effect and the potential molecular mechanisms of HMF on the alleviation of MS from the perspective of gut microecology and metabolome.…”

Nobiletin Ameliorates Hepatic Lipid Deposition, Oxidative Stress, and Inflammation by Mechanisms That Involve the Nrf2/NF-κB Axis in Nonalcoholic Fatty Liver Disease

“…Multiple researches have reported the positive effects of NOB on NAFLD. For instance, NOB exerts an antisteatotic effect on the liver by regulating the expression of adiponectin receptor 1 and NADPH oxidase subunit gp91 phox restoring aberrant hepatic circadian rhythm, enhancing lipophagy, as well as targeting gut microbiota and myristoleic acid metabolism . Moreover, our previous study also revealed that NOB mitigates the typical symptoms of NAFLD mice modeled by HFD through reducing the levels of hepatic lipids and serum pro-inflammatory cytokines .…”

Design, synthesis and evaluation of a myricetin and nobiletin hybrid compound for alleviating hyperuricemia based on metabolomics and gut microbiota

“…18 Nobiletin, a natural polymethoxy avonoid derived from citrus peels, has been widely reported for its benecial effects including anti-hyperglycemia, antidiabetic, anti-tumor, anti-inammatory, hepatic-protective functions, as well as for its improvement of mitochondrial function and memory loss. [19][20][21][22] Additional, in a rat model of hyperuricemia, orally dosed amorphous solid dispersion of nobiletin showed an improved hypouricemic effect by a 16% reduction in the plasma uric acid level compared with orally administered crystalline nobiletin. 23 Although research into the synthesis and structural modication of myricetin and nobiletin has been extensively carried out, little information has been available on the synthesis of hybrid compounds consisting of myricetin and nobiletin.…”