Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury

Khambu, Bilon; Li, Tiangang; Yan, Shengmin; Yu, Changshun; Chen, Xiaoyun; Goheen, Michael P.; Li, Yong; Ji, Lin; Cummings, Oscar W.; Lee, Youngmin A.; Friedman, Scott; Dong, Zheng; Feng, Gen Sheng; Wu, Shangwei; Yin, Xiao Ming

doi:10.1002/hep.30407

Cited by 46 publications

(72 citation statements)

References 47 publications

(95 reference statements)

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“…S6C-D). These results suggest that hepatic composition of BAs is altered but is less sensitive to ABX treatment in Atg5 ∆hep mice [11].…”

Section: Liver-specific Deletion Of Atg5 Altered the Composition Of Imentioning

confidence: 74%

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Gut dysbiosis protects against liver injury in autophagy deficient mice by FXR-FGF15 feedback signaling

Yan

Khambu

Chen

et al. 2020

Preprint

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Objective:The gut microbiota (GM) can have complicated and often undetermined interactions with the function of many organs in the body. GM is altered in a variety of liver diseases, but the significance of such changes on the liver disease is still unclear. Hepatic autophagy deficiency causes liver injury accompanied with cholestasis. Here, we investigated the impact of such hepatic changes on GM and in turn the effect of gut dysbiosis on liver injury. Design:Fecal microbiota from mice with liver-specific loss of autophagy-related gene 5 (Atg5), Atg5 ∆hep mice, were analyzed by 16S sequencing. Antibiotics (ABX) was used to modulate GM in mice.Cholestyramine was used to reduce the enterohepatic bile acid (BA) level. The functional role of fibroblast growth factor 15 (FGF15) and ileal farnesoid X receptor (FXR) was examined in mice overexpressing FGF15 gene, or given a fibroblast growth factor receptor 4 (FGFR4) inhibitor. Results:The composition of GM was significantly changed with a notable increase of BA-metabolizing bacteria in Atg5 ∆hep mice, leading to a lower proportion of tauro-conjugated BAs and a higher proportion of unconjugated BAs in the intestine, which markedly activated ileal FXR with an increased expression of FGF15. ABX or cholestyramine treatment exacerbated liver injury and ductular reaction, and decreased FGF15 expression, whereas modulating FGF15 signaling altered liver phenotypes in the autophagy-deficient mice. Conclusion:Gut dysbiosis can remedy liver injury in Atg5 ∆hep mice through the FXR-FGF15 signaling.Antibiotics use in the condition of liver injury may have unexpected adverse consequences via the gutliver axis.

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“…S6C-D). These results suggest that hepatic composition of BAs is altered but is less sensitive to ABX treatment in Atg5 ∆hep mice [11].…”

Section: Liver-specific Deletion Of Atg5 Altered the Composition Of Imentioning

confidence: 74%

“…Atg5 and Atg7, causes severe liver injury, fibrosis, and tumorigenesis [9,10]. Our previous study demonstrates autophagy deficiency-induced liver injury is accompanied with altered BA metabolism, cholestatic injury and impaired hepatic farnesoid X receptor (FXR) activity [11].…”

Section: Introductionmentioning

confidence: 99%

Gut dysbiosis protects against liver injury in autophagy deficient mice by FXR-FGF15 feedback signaling

Yan

Khambu

Chen

et al. 2020

Preprint

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“…Hepatocellular neoplasia often occurs in the setting of chronic injury and inflammation, which is present in autophagy-deficient livers 2, 20 . Persistent inflammation is also known to promote and exacerbate malignancy.…”

Section: Resultsmentioning

confidence: 99%

“…Atg7F/F was obtained from Dr. Komatsu Masaaki (Nigata University, Japan). These mice were backcrossed with C57BL/6J for another 10 generations as described previously 2, 20 . Albumin-Cre mice were obtained from the Jackson Laboratory(Bar Harbor, ME).…”

Section: Methodsmentioning

confidence: 99%

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The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors

Khambu

Hong

Liu

et al. 2019

Preprint

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AbstractAutophagy is an intracellular lysosomal degradative pathway important for tumor surveillance. Autophagy deficiency can lead to tumorigenesis. Autophagy is also known to be important for the aggressive growth of tumors, yet the mechanism that sustains the growth of autophagy-deficient tumors is not known. We previously reported that progression of hepatic tumors developed in autophagy-deficient livers required high mobility group box 1 (HMGB1) that is released from autophagy-deficient hepatocytes. However, the mechanism by which HMGB1 promotes hepatic tumorigenesis is not understood. In this study we examined the pathological features of the hepatic tumors and the mechanism of HMGB1-mediated tumorigenesis using liver-specific autophagy-deficient (Atg7-/-) and Atg7-/-/Hmgb1-/- mice. We found that in Atg7-/- mice the tumors cells were still deficient in autophagy and could also release HMGB1. Histological analysis using cell-specific markers suggested that fibroblast and ductular cells were present only outside the tumor whereas macrophages were present both inside and outside the tumor. Genetic deletion of HMGB1 or one of its receptors, receptor for advanced glycated end product (Rage), retarded liver tumor development. In addition, we found that expression of RAGE was only on ductual cells and Kupffer’s cells but not on hepatoctyes, which suggested that HMGB1 might promote hepatic tumor growth through a paracrine mode that altered the tumor microenvironment. Furthermore, HMGB1 and RAGE enhanced the proliferation capability of the autophagy-deficient hepatocytes and tumors. Finally, RNAseq analysis of the tumors indicated that HMGB1 induced a much broad changes in tumors. In particular, genes related to mitochondrial structures or functions were enriched among those differentially expressed in tumors in the presence or absence of HMGB1, revealing a potential key role of mitochondria in sustaining the growth of autophagy-deficient liver tumors via HMGB1 stimulation.

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Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid

Wu,

Liu,

Xia

et al. 2023

Advanced Science

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Although the dysregulation of bile acid (BA) composition has been associated with fibrosis progression, its precise roles in liver fibrosis is poorly understood. This study demonstrates that solute carrier family 27 member 5 (SLC27A5), an enzyme involved in BAs metabolism, is substantially downregulated in the liver tissues of patients with cirrhosis and fibrosis mouse models. The downregulation of SLC27A5 depends on RUNX family transcription factor 2 (RUNX2), which serves as a transcriptional repressor. The findings reveal that experimental SLC27A5 knockout (Slc27a5−/−) mice display spontaneous liver fibrosis after 24 months. The loss of SLC27A5 aggravates liver fibrosis induced by carbon tetrachloride (CCI4) and thioacetamide (TAA). Mechanistically, SLC27A5 deficiency results in the accumulation of unconjugated BA, particularly cholic acid (CA), in the liver. This accumulation leads to the activation of hepatic stellate cells (HSCs) by upregulated expression of early growth response protein 3 (EGR3). The re‐expression of hepatic SLC27A5 by an adeno‐associated virus or the reduction of CA levels in the liver using A4250, an apical sodium‐dependent bile acid transporter (ASBT) inhibitor, ameliorates liver fibrosis in Slc27a5−/− mice. In conclusion, SLC27A5 deficiency in mice drives hepatic fibrosis through CA‐induced activation of HSCs, highlighting its significant implications for liver fibrosis treatment.

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Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury

Cited by 46 publications

References 47 publications

Gut dysbiosis protects against liver injury in autophagy deficient mice by FXR-FGF15 feedback signaling

Gut dysbiosis protects against liver injury in autophagy deficient mice by FXR-FGF15 feedback signaling

The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors

Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid

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