Xiaoyuan Wang,Yinchuan Lv,Xin Qiang,Shumin Liang,Ruosi Li,Jing Zhan,Jiaying Liu
The disruption of per- and polyfluoroalkyl substances (PFASs) on bile acid (BA) homeostasis has raised public concerns, making the evaluation of their effects and underlying mechanisms a high priority. Although the use of perfluorooctanoic acid (PFOA) has been restricted, it remains a widespread legacy PFAS in the environment. Concurrently, the use of its prevalent short-chain alternative, perfluorobutanoic acid (PFBA), is increasing, yet the toxicity assessment of PFBA remains inadequate. In this study, C57BL/6N mice were exposed to PFOA and PFBA (0.4 or 10 mg/kg body weight) by gavage for 28 days. The results showed that both PFOA and PFBA significantly increased hepatic weight, although PFBA exhibited lower bioaccumulation than PFOA in the liver. Targeted metabolomics revealed that PFOA significantly decreased total BA levels and altered their composition. Conversely, PFBA, without significantly altering total BA levels, notably changed their composition, such as increasing the proportion of cholic acid. Further investigations using in vivo and in vitro assays suggested that PFOA inhibited the expression of Cyp7A1, a key BA synthetase, potentially via PPARα activation, thereby reducing BA levels. In contrast, PFBA enhanced Cyp7A1 expression, associated with the inhibition of intestinal Farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) pathway. This study evaluated the differences in the BA-interfering effects of PFOA and PFBA and shed light on the potential mechanisms, which will provide new insights into the health risks of legacy PFASs and their alternatives.
Lonicera japonica Thunb. is widely used in Asian countries as a food ingredient to make healthy drinks, with lonicerin, a flavone O -glycoside, as a predominant bioactive compound. This study investigated lonicerin’s effects on high-fat diet-induced hepatic steatosis in mice, compared to its aglycone luteolin. Results showed that lonicerin significantly reduced diet-induced body weight gain and hepatic lipid accumulation in mice, demonstrating greater efficacy than luteolin. This lipid-lowering effect was due to inhibited hepatic fatty acid (FA) biosynthesis and promoted fecal lipid excretion. Moreover, lonicerin favorably modulated gut microbiota by increasing Dubosiella , Eubacterium_brachy_group , and Bilophila , while reducing the pathogenic Desulfovibrionaceae . These changes led to elevated short-chain fatty acid production and altered fecal bile acid (BA) profiles, likely activating the intestinal FXR-FGF15 pathway to inhibit hepatic FA synthesis. In conclusion, lonicerin alleviated diet-induced hepatic steatosis by promoting fecal lipid excretion and inhibiting hepatic FA biosynthesis through modulating the gut microbiota-BA-intestinal FXR axis.
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