Limb expression 1-like (LIX1L) protein promotes cholestatic liver injury by regulating bile acid metabolism

Li, Jie; Zhu, Xiaoyun; Zhang, Meihui; Zhang, Yanqiu; Ye, Shengtao; Leng, Yingrong; Yang, Ting; Kong, Ling‐Yi; Zhang, Hao

doi:10.1016/j.jhep.2021.02.035

Cited by 36 publications

(24 citation statements)

References 43 publications

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“…IHC is a clinical syndrome caused by the accumulation of bile in the liver [ 28 ]. Excluding biliary obstruction, it is often induced by viral hepatitis, drug-induced liver damage, genetic factors, and pregnancy [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanism and Active Components of Qingre Lidan Tablets Alleviate Intrahepatic Cholestasis by Activating the Farnesoid X Receptor

Xia

Yan

Chang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. Qingre Lidan tablets (QLTs) are a compound preparation of Chinese medicine that have long been used clinically to treat poor bile circulation caused by the inflammation and obstruction of the gallbladder and bile duct and to relieve jaundice and other symptoms. However, its material basis and mechanism are still unclear. The purpose of this study was to investigate the mechanism and active components of QLTs for treating intrahepatic cholestasis (IHC) in rat models. Methods. In vivo experiments verified the effect of QLTs on alpha-naphthyl isothiocyanate (ANIT)-induced IHC models in rats. The mRNA and protein expression levels of farnesoid X receptor (FXR), bile salt export pump (BSEP), and multidrug-associated protein 2 (MRP2) in the rat liver were detected. UPLC/Q-TOF-MS was used to separate and identify the monomers in QLTs, and a dual-luciferase reporter assay was used to select effective the monomers that stimulate FXR. Among the selected monomers, baicalein was used as a representative to verify the effect on rat IHC models. Results. QLTs and baicalein significantly reduced the serum biochemical indicators reflecting the changes in liver function among IHC rats and remitted the ANIT-induced liver histopathological changes. The expression levels of FXR, BSEP, and MRP2 in the liver were significantly increased after QLT treatment in a dose-dependent manner. Moreover, six types of active components that activate FXR were selected in QLTs, namely baicalein, wogonin, baicalein II, emodin, dibutyl phthalate, and diisooctyl phthalate. Conclusions. QLTs and the active component, baicalein, can alleviate IHC in model rats.

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Section: Discussionmentioning

confidence: 99%

Mechanism and Active Components of Qingre Lidan Tablets Alleviate Intrahepatic Cholestasis by Activating the Farnesoid X Receptor

Xia

Yan

Chang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…Previous studies have implicated its role in bile acid synthesis in cholestatic liver injury [16] and in cancer cell proliferation [17], protein functions that have not been shown to significantly affect mitral morphogenesis. To uncover LIX1L-mediated pathways, an additional two-hybrid screen was performed using full-length LIX1L protein as bait against the same human heart library.…”

Section: Identification Of Dchs1-lix1l-sept9 (Dls) Protein Complexmentioning

confidence: 99%

DCHS1, Lix1L, and the Septin Cytoskeleton: Molecular and Developmental Etiology of Mitral Valve Prolapse

Moore

Fulmer

et al. 2022

JCDD

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Mitral valve prolapse (MVP) is a common cardiac valve disease that often progresses to serious secondary complications requiring surgery. MVP manifests as extracellular matrix disorganization and biomechanically incompetent tissues in the adult setting. However, MVP has recently been shown to have a developmental basis, as multiple causal genes expressed during embryonic development have been identified. Disease phenotypes have been observed in mouse models with human MVP mutations as early as birth. This study focuses on the developmental function of DCHS1, one of the first genes to be shown as causal in multiple families with non-syndromic MVP. By using various biochemical techniques as well as mouse and cell culture models, we demonstrate a unique link between DCHS1-based cell adhesions and the septin-actin cytoskeleton through interactions with cytoplasmic protein Lix1-Like (LIX1L). This DCHS1-LIX1L-SEPT9 axis interacts with and promotes filamentous actin organization to direct cell-ECM alignment and valve tissue shape.

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“…LIX1L regulates the levels of miR-191-3p, a microRNA that downregulates transcription factor liver receptor homolog-1 (LRH-1), thereby inhibiting Cyp7a1 and Cyp8b1 expression, two enzymes required for BA synthesis. Based on these data, Li et al [ 118 ], recently showed that an AAV vector overexpressing miR-191-3p was able to ameliorate cholestasis in FVB Abcb4 -/- mice by direct repression of LRH-1 expression, thereby reducing de novo BA synthesis [ 118 ]. Another potential target for reducing liver fibrosis through gene therapy of cholestatic disorders is the suppression of the neurokinin 1 receptor (NK1R) axis as well as transforming growth factor-β1 (TGF-β1)/miR-31 signaling.…”

Section: Gene Therapymentioning

confidence: 99%

Gene Therapy for Acquired and Genetic Cholestasis

Martínez-García

Molina

González‐Aseguinolaza

et al. 2022

Biomedicines

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Cholestatic diseases can be caused by the dysfunction of transporters involved in hepatobiliary circulation. Although pharmacological treatments constitute the current standard of care for these diseases, none are curative, with liver transplantation being the only long-term solution for severe cholestasis, albeit with many disadvantages. Liver-directed gene therapy has shown promising results in clinical trials for genetic diseases, and it could constitute a potential new therapeutic approach for cholestatic diseases. Many preclinical gene therapy studies have shown positive results in animal models of both acquired and genetic cholestasis. The delivery of genes that reduce apoptosis or fibrosis or improve bile flow has shown therapeutic effects in rodents in which cholestasis was induced by drugs or bile duct ligation. Most studies targeting inherited cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), have focused on supplementing a correct version of a mutated gene to the liver using viral or non-viral vectors in order to achieve expression of the therapeutic protein. These strategies have generated promising results in treating PFIC3 in mouse models of the disease. However, important challenges remain in translating this therapy to the clinic, as well as in developing gene therapy strategies for other types of acquired and genetic cholestasis.

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Limb expression 1-like (LIX1L) protein promotes cholestatic liver injury by regulating bile acid metabolism

Cited by 36 publications

References 43 publications

Mechanism and Active Components of Qingre Lidan Tablets Alleviate Intrahepatic Cholestasis by Activating the Farnesoid X Receptor

Mechanism and Active Components of Qingre Lidan Tablets Alleviate Intrahepatic Cholestasis by Activating the Farnesoid X Receptor

DCHS1, Lix1L, and the Septin Cytoskeleton: Molecular and Developmental Etiology of Mitral Valve Prolapse

Gene Therapy for Acquired and Genetic Cholestasis

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