Journal of translational medicine · 2026
Hepatic FXR deficiency exacerbates dyslipidemia by disrupting the gut-liver axis via bile acid disorder and gut microbiota dysbiosis.
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Liu Yunlu, Wang Jiahua, Zhang Chenchen, Li Zhiyong, Nie Yinglan, Hu Yanhong, Liu Chuan, Tu Ya
Аннотация
BACKGROUND: Dyslipidemia, a core component of metabolic syndrome, is mechanistically linked to gut-liver axis dysfunction, in which the Farnesoid X receptor (FXR) is a master regulator. However, the initiating role of hepatocyte-derived FXR signaling in this process remains poorly defined.
METHODS: To investigate this, we employed an adeno-associated virus serotype 8 (AAV8)-CRISPR-CasRx system to achieve hepatocyte-specific Fxr knockdown in mice subjected to a 16-week high-fat diet. Systemic metabolic phenotypes, hepatic steatosis, and intestinal barrier integrity were comprehensively evaluated. Furthermore, we assessed molecular alterations in the gut-liver axis via quantitative real-time PCR and Western blot, characterized the gut microbiota using full-length 16S rRNA gene sequencing, and profiled the fecal bile acid pool using targeted metabolomics.
RESULTS: Hepatic FXR deficiency synergized with dietary stress to exacerbate weight gain, dyslipidemia, and hepatic steatosis. Mechanistically, FXR loss led to a marked upregulation of CYP7A1 and suppression of SHP, disrupting bile acid homeostasis and remodeling the fecal bile acid pool. This reconstituted bile acid pool triggered a cascade of gut-liver axis dysfunction, characterized by an attenuated intestinal FXR-FGF15 feedback loop, compromised gut barrier integrity, and profound microbial dysbiosis. Concurrently, hepatic lipid metabolism was reprogrammed toward a lipogenic state, evidenced by upregulation of SREBP1c and downregulation of PPARα.
CONCLUSIONS: Collectively, this study indicates that hepatic FXR deficiency exacerbates dyslipidemia by disrupting the gut-liver axis, primarily via bile acid disorder and gut microbiota dysbiosis. This establishes hepatic FXR as a crucial guardian of metabolic homeostasis and identifies the gut-liver axis as a pivotal target for therapeutic intervention.
METHODS: To investigate this, we employed an adeno-associated virus serotype 8 (AAV8)-CRISPR-CasRx system to achieve hepatocyte-specific Fxr knockdown in mice subjected to a 16-week high-fat diet. Systemic metabolic phenotypes, hepatic steatosis, and intestinal barrier integrity were comprehensively evaluated. Furthermore, we assessed molecular alterations in the gut-liver axis via quantitative real-time PCR and Western blot, characterized the gut microbiota using full-length 16S rRNA gene sequencing, and profiled the fecal bile acid pool using targeted metabolomics.
RESULTS: Hepatic FXR deficiency synergized with dietary stress to exacerbate weight gain, dyslipidemia, and hepatic steatosis. Mechanistically, FXR loss led to a marked upregulation of CYP7A1 and suppression of SHP, disrupting bile acid homeostasis and remodeling the fecal bile acid pool. This reconstituted bile acid pool triggered a cascade of gut-liver axis dysfunction, characterized by an attenuated intestinal FXR-FGF15 feedback loop, compromised gut barrier integrity, and profound microbial dysbiosis. Concurrently, hepatic lipid metabolism was reprogrammed toward a lipogenic state, evidenced by upregulation of SREBP1c and downregulation of PPARα.
CONCLUSIONS: Collectively, this study indicates that hepatic FXR deficiency exacerbates dyslipidemia by disrupting the gut-liver axis, primarily via bile acid disorder and gut microbiota dysbiosis. This establishes hepatic FXR as a crucial guardian of metabolic homeostasis and identifies the gut-liver axis as a pivotal target for therapeutic intervention.