Liver international : official journal of the International Association for the Study of the Liver · 2026
BBOX1 Deficiency Exacerbates Liver Fibrosis Through Carnitine Biosynthesis Disruption Rescued by Carnitine Supplementation.
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Zhan Yuling, Wang Ying, Wei Tianlong, He Yingyuan, Lu Shiyi, Shao Qianqian, Ma Shasha, Zhang Li, Mei Xiaoqiang, Gao Yu
Аннотация
BACKGROUND AND AIM: Liver fibrosis is a major global health burden with limited treatments. Emerging evidence suggests that metabolic dysregulation can create a state that makes the liver more prone to fibrosis. Carnitine, synthesized by γ-butyrobetaine hydroxylase (BBOX1), is crucial for fat metabolism, but the role of the BBOX1-carnitine axis in liver fibrosis is unclear. This study aimed to elucidate the functional impact of BBOX1 deficiency on hepatic fibrogenesis and to delineate the underlying mechanistic pathway.
METHODS: We analysed human liver transcriptomic data. Bbox1 knockout (KO) mice and wild-type (WT) littermates were subjected to thioacetamide (TAA)-induced liver fibrosis, with or without dietary L-carnitine supplementation. Comprehensive analyses included metabolomic and transcriptomic profiling, histopathological evaluation, and focused investigation of calcium-dependent signalling pathways.
RESULTS: BBOX1 expression was significantly downregulated in human cirrhotic livers and correlated with reduced systemic carnitine levels. Bbox1-KO mice exhibited profound hepatic carnitine depletion and a metabolically primed state. With TAA challenge, KO mice developed exacerbated liver fibrosis and inflammation compared to WT controls. This susceptibility was driven by the aberrant activation of the TRPC6-Ca2+/CAMK2B-inflammatory signalling axis. Moreover, dietary L-carnitine supplementation completely rescued the aggravated fibrotic phenotype in KO mice.
CONCLUSION: BBOX1 is a key regulator of liver carnitine metabolism. Its deficiency creates a pro-fibrotic state by abnormally activating the TRPC6-Ca2+/CAMK2B pathway. Our findings position carnitine as a protector of calcium balance in the liver and identify L-carnitine supplementation as a potential targeted treatment to slow fibrosis progression.
METHODS: We analysed human liver transcriptomic data. Bbox1 knockout (KO) mice and wild-type (WT) littermates were subjected to thioacetamide (TAA)-induced liver fibrosis, with or without dietary L-carnitine supplementation. Comprehensive analyses included metabolomic and transcriptomic profiling, histopathological evaluation, and focused investigation of calcium-dependent signalling pathways.
RESULTS: BBOX1 expression was significantly downregulated in human cirrhotic livers and correlated with reduced systemic carnitine levels. Bbox1-KO mice exhibited profound hepatic carnitine depletion and a metabolically primed state. With TAA challenge, KO mice developed exacerbated liver fibrosis and inflammation compared to WT controls. This susceptibility was driven by the aberrant activation of the TRPC6-Ca2+/CAMK2B-inflammatory signalling axis. Moreover, dietary L-carnitine supplementation completely rescued the aggravated fibrotic phenotype in KO mice.
CONCLUSION: BBOX1 is a key regulator of liver carnitine metabolism. Its deficiency creates a pro-fibrotic state by abnormally activating the TRPC6-Ca2+/CAMK2B pathway. Our findings position carnitine as a protector of calcium balance in the liver and identify L-carnitine supplementation as a potential targeted treatment to slow fibrosis progression.