Yinchen Linggui Zhugan decoction ameliorates high fat diet-induced nonalcoholic fatty liver disease by modulation of SIRT1/Nrf2 signaling pathway and gut microbiota

Abstract

Yinchen Linggui Zhugan decoction (YLZD) is an effective and classical traditional herbal prescription for treating the nonalcoholic fatty liver disease (NAFLD) and has been proven to be effective in the regulation of lipid metabolism disorder and attenuate inflammation for a NAFLD rat model. However, the exact underlying mechanism has not been elucidated. In the current study, a NAFLD rat model was established using a high-fat diet (HFD) for 10 weeks, followed by YLZD treatment with 1.92 g/kg/day for 4 weeks to explore the mechanisms of YLZD. Our results showed that YLZD decreased the hepatic lipid deposition, restored the liver tissue pathological lesions, inhibited the expression of oxidative stress, and decreased the inflammatory cytokines levels. Meanwhile, the genes and proteins expressions of SIRT1/Nrf2 signaling pathway together with downstream factors including HO-1 and NQO1 were elevated in the YLZD treated NAFLD rats. For further elaborating the upstream mechanism, short-chain fatty acids (SCFAs) in serum and feces were measured by liquid chromatograph mass spectrometer and gas chromatograph mass spectrometer, and the differences in gut microbiota of rats in each group were analyzed through high-throughput sequencing of 16S rRNA. The results demonstrated that the contents of butyric acid (BA) and total SCFAs in YLZD-treated NAFLD rats were significantly increased in serum and feces. 16S rRNA sequencing analysis illustrated that YLZD intervention led to a modification of the gut microbiota composition, with a decrease of Oribacterium, Lactobacillus and the ratio of Firmicutes/Bacteroides, as well as the increase in SCFAs-producing bacteria such as Christensenellaceae, Clostridia, Muribaculaceae, and Prevotellaceae. Spearman rank correlation analysis indicated that BA and total SCFAs were negatively co-related with oxidative stress-related factors and inflammatory cytokines, while they were positively co-related with SIRT1/Nrf2 pathway related genes and proteins. Furthermore, in vitro study confirmed that BA effectively reduced oxidative stress by activating SIRT1/Nrf2 signaling pathway in L02 cells. Together, the present data revealed YLZD could ameliorate HFD-induced NAFLD in rats by the modulation of SIRT1/Nrf2 signaling pathway and gut microbiota.

Exploring the Regulatory Effect of Tegillarca granosa Polysaccharide on High‐Fat Diet‐Induced Non‐Alcoholic Fatty Liver Disease in Mice Based on Intestinal Flora

“…We conducted a Spearman correlation analysis to understand the association between differentially enriched microorganisms and lipid metabolism, antioxidant properties, inflammatory parameters, and SCFAs. [ 27 ] The results are shown in Figure 9B,C. Faecalibaculum , norank_f_Erysipelotrichaceae , Enterorhabdus , Candidatus_Saccharimonas , and Monoglobus were positively correlated with liver lipid metabolism factors (TG, TC, and NEFA), oxidation‐related factors (MDA), inflammation‐related factors (IL‐6, IL‐1β, and TNF‐α), and negatively correlated with SOD and GSH‐Px ( p < 0.05).…”

Vitamin D improves hepatic steatosis in NAFLD via regulation of fatty acid uptake and β-oxidation

“…HFD is a well-established modeling method, which can lead to the development of metabolic syndrome, hepatic steatosis, and NASH in experimental animals ( 78 ). The duration of dietary intake and VD treatment in previous studies ranges from 10 weeks to 22 weeks and 3 weeks to 10 weeks, respectively, thus impacting the severity of NAFLD and effect of treatment ( 56 , 79 – 81 ). In the present study, rats were fed with an HFD for 14 weeks, and the NAFLD model was determined by sacrifice at Week 7.…”

Effects of plant natural products on metabolic-associated fatty liver disease and the underlying mechanisms: a narrative review with a focus on the modulation of the gut microbiota

“…Yinchen Linggui Zhugan decoction can enrich the SCFA-producing bacteria Christensenellaceae, Muribaculateae and Prevotellaceae to increase the gut SCFA content, especially Christensenellaceae, which is closely correlated with acetic acid, butyric acid and total SCFAs. The increase in butyric acid not only provides energy to gut epithelial cells but also activates the silent information regulator 1/Nrf2 signaling pathway and increases the expression of downstream antioxidant factors, which in turn ameliorates oxidative stress ( Jiang et al., 2022b ). These results suggest that Yinchen Linggui Zhugan decoction can alleviate MAFLD by modulating the gut microbiota and butyric acid levels.…”