Hepatobiliary & pancreatic diseases international : HBPD INT · 2026
CPT1A-driven metabolic reprogramming serves as a compensatory adaptation to sustain energy homeostasis in obstructive cholestasis.
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Lu Zhong-Shan, Hu Xiao-Yan, Zhou Wei, Xu Yan, Ye Qi-Fa, Ye Shao-Jun
Аннотация
BACKGROUND: Cholestatic liver disease is characterized by severe weight loss that remains a major clinical challenge due to limited therapeutic efficacy. This metabolic dysregulation may stem from impaired energy homeostasis, yet the underlying mechanisms remain poorly understood. Fatty acid oxidation (FAO) is a critical energy-producing pathway in the liver, and its adaptation under cholestatic stress may determine whether patients experience metabolic resilience or progressive cachexia.
METHODS: Adult male Sprague-Dawley rats and New Zealand rabbits underwent common bile duct ligation (BDL) or sham surgery. Postoperative assessments included serum biochemistry, hepatic histopathology, and immunohistochemical analyses for inflammatory and regenerative markers. Additional BDL rats received pharmacological interventions targeting carnitine palmitoyltransferase 1A (CPT1A), such as etomoxir or baicalin or multidrug resistance-associated protein 3 (MRP3) (DM‑4107). Protein expression of key mediators of bilirubin transport, metabolism, and fatty acid oxidation was analyzed by Western blot.
RESULTS: Both species developed significant cholestasis, yet showed divergent outcomes. Rats exhibited adaptive weight recovery, coupled with MRP3 upregulation and CPT1A induction, promoting bilirubin clearance and FAO enhancement. Conversely, rabbits showed progressive weight loss, with sustained MRP3 suppression and failed CPT1A induction, leading to persistent bilirubin retention and impaired FAO. Pharmacological modulation confirmed causality: CPT1A inhibition exacerbated injury and weight loss, while its activation improved recovery; similarly, MRP3 inhibition aggravated cholestasis and metabolic dysfunction.
CONCLUSIONS: This study identifies CPT1A-mediated FAO as a metabolic determinant of nutritional resilience in cholestasis. The failure to activate compensatory bilirubin export and FAO underlies progressive cachexia. Pharmacological targeting of this pathway shows therapeutic promise for cholestatic patients with refractory weight loss and metabolic impairment.
METHODS: Adult male Sprague-Dawley rats and New Zealand rabbits underwent common bile duct ligation (BDL) or sham surgery. Postoperative assessments included serum biochemistry, hepatic histopathology, and immunohistochemical analyses for inflammatory and regenerative markers. Additional BDL rats received pharmacological interventions targeting carnitine palmitoyltransferase 1A (CPT1A), such as etomoxir or baicalin or multidrug resistance-associated protein 3 (MRP3) (DM‑4107). Protein expression of key mediators of bilirubin transport, metabolism, and fatty acid oxidation was analyzed by Western blot.
RESULTS: Both species developed significant cholestasis, yet showed divergent outcomes. Rats exhibited adaptive weight recovery, coupled with MRP3 upregulation and CPT1A induction, promoting bilirubin clearance and FAO enhancement. Conversely, rabbits showed progressive weight loss, with sustained MRP3 suppression and failed CPT1A induction, leading to persistent bilirubin retention and impaired FAO. Pharmacological modulation confirmed causality: CPT1A inhibition exacerbated injury and weight loss, while its activation improved recovery; similarly, MRP3 inhibition aggravated cholestasis and metabolic dysfunction.
CONCLUSIONS: This study identifies CPT1A-mediated FAO as a metabolic determinant of nutritional resilience in cholestasis. The failure to activate compensatory bilirubin export and FAO underlies progressive cachexia. Pharmacological targeting of this pathway shows therapeutic promise for cholestatic patients with refractory weight loss and metabolic impairment.