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Background <p>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.</p> Methods <p>To investigate this, we employed an adeno-associated virus serotype 8 (AAV8)-CRISPR-CasRx system to achieve hepatocyte-specific <i>Fxr</i> 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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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Hepatic FXR deficiency exacerbates dyslipidemia by disrupting the gut-liver axis via bile acid disorder and gut microbiota dysbiosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Yunlu Liu,
  • Jiahua Wang,
  • Chenchen Zhang,
  • Zhiyong Li,
  • Yinglan Nie,
  • Yanhong Hu,
  • Chuan Liu,
  • Ya Tu

摘要

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.