Hyaluronan in liver fibrosis: basic mechanisms, clinical implications, and therapeutic targets

Kim, Jieun; Seki, Ekihiro

doi:10.1097/hc9.0000000000000083

Cited by 10 publications

(6 citation statements)

References 83 publications

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“…We previously showed that proglumide decreases NASH steatosis by interacting as a partial agonist at FXR ( 39 ). Many of the genes that were significantly downregulated in the livers of DDC-fed mice treated with proglumide were responsible for fibrosis ( Upk3b and HAPLN1 ) ( 40 , 41 ) or inflammation ( Il1f9 ) ( 42 ). Other significantly downregulated genes by proglumide have been implicated as biomarkers in the progression to cirrhosis, such as A1BG (that codes for Alpha-1-B Glycoprotein; 43 ), Ppbp (that codes for proplatelet basic protein; 44 ), and CDC6 (Cell Division Cycle 6; 45 ).…”

Section: Resultsmentioning

confidence: 99%

Implicating the cholecystokinin B receptor in liver stem cell oncogenesis

Gay,

Drda,

Chen

et al. 2024

American Journal of Physiology-Gastrointestinal and Liver Physi

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Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths worldwide. Chronic inflammation and fibrosis are the greatest risk factors for the development of HCC. Although the cell of origin for HCC is uncertain, many theories believe this cancer may arise from liver progenitor cells or stem cells. Here, we describe the activation of hepatic stem cells that over-express the cholecystokinin-B receptor (CCK-BR) after liver injury with either a DDC diet (0.1% 3, 5-diethoxy-carbonyl 1,4-dihydrocollidine) or a NASH-inducing CDE diet (choline deficient ethionine) in murine models. Pharmacologic blockade of the CCK-BR with a receptor antagonist proglumide or knockout of the CCK-BR in genetically engineered mice during the injury diet reduces the expression of hepatic stem cells and prevents the formation of 3-dimensional tumorspheres in culture. RNA sequencing of livers from DDC-fed mice treated with proglumide or DDC-fed CCK-BR knockout mice showed downregulation of differentially expressed genes involved in cell proliferation and oncogenesis and upregulation of tumor suppressor genes compared to controls. Inhibition of the CCK-BR decreases hepatic transaminases, fibrosis, cytokine expression, and alters the hepatic immune cell signature rendering the liver microenvironment less oncogenic. Furthermore, proglumide hastened recovery after liver injury by reversing fibrosis and improving markers of synthetic function. Proglumide is an older drug that is orally bioavailable and being repurposed for liver conditions. These findings support a promising therapeutic intervention applicable to patients to prevent the development of HCC and decrease hepatic fibrosis.

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Section: Resultsmentioning

confidence: 99%

Implicating the cholecystokinin B receptor in liver stem cell oncogenesis

Gay,

Drda,

Chen

et al. 2024

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In addition, some COVID-19 patients were combined with bacterial pneumonia, the slower decline in HA levels may be due to a continued inflammatory process under the double whammy of virus and bacteria ( Misra et al., 2015 ). Since HA has been used as an important diagnostic index to evaluate the degree of hepatic fibrosis, we speculate that persistently high HA levels may be associated with pulmonary consequences, such as lung consolidation and fibrosis ( Bazdyrev et al., 2021 ; Kim and Seki, 2023 ). This evidence highlights the need to reassess HA levels within 3 to 6 months of infection, especially in patients with long COVID.…”

Section: Discussionmentioning

confidence: 99%

Elevated hyaluronic acid levels in severe SARS-CoV-2 infection in the post-COVID-19 era

Li,

Cui,

Zhu

et al. 2024

Front. Cell. Infect. Microbiol.

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ObjectiveHuman identical sequences of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) promoted the coronavirus disease 2019 (COVID-19) progression by upregulating hyaluronic acid (HA) via NamiRNA-enhancer network, based on previous experimental research. This study aimed to investigate the predictive value of HA for the severity of SARS-CoV-2 infection in the post-COVID-19 era.MethodsA total of 217 consecutive patients with COVID-19 were enrolled at Beijing Ditan Hospital between July 2023 and October 2023. HA levels were analyzed using biochemical detector. Logistic regression analysis was used to screen independent factors for severe COVID-19. The predictive performance of HA for severe infection was assessed by ROC curve. Furthermore, the relationship between HA levels and COVID-19 severity was investigated using multivariate logistic regression models after adjustment for potential confounders.ResultsAccording to the cut-off value of HA, COVID-19 patients were divided into HA < 90 ng/mL group (80 cases) and HA ≥ 90 ng/mL group (137 cases). High HA levels were positively associated with the severe SARS-CoV-2 infection, including elevated inflammatory indicators, severe lung involvement, prolonged clinical course, and higher incidence of respiratory failure and death (P < 0.05). Logistic regression analysis suggested that HA was an independent predictor of severe COVID-19 (OR = 4.540, 95% CI = 2.105-9.790, P < 0.001). ROC curve analysis showed that the AUC of HA for severe infection was 0.724. HA levels were significantly higher in COVID-19 cases compared to the healthy population (123.9 (82.6, 174.1) vs. 50.5 (37.8, 66.8), P < 0.001), but similar to those with non-SARS-CoV-2 lung infection (121.6 (78.5, 175.6) vs. 106.0 (66.5, 149.7), P = 0.244). We also found that the first COVID-19 infections had higher HA levels (118.8 (79.5, 174.3) vs. 85.0 (61.1, 128.8), P < 0.001) and a higher proportion of severe infection (37.1% vs. 21.3%, P = 0.043) than re-infections. However, HA expression failed to fully return to normal levels with infection recovery (204.7 (152.9, 242.2) vs. 97.0 (69.3, 137.3), P < 0.001).ConclusionHA was associated with severe SARS-CoV-2 infection and could be used as a novel serum biomarker to predict the risk of COVID-19 progression in the post-COVID-19 era.

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“…Ligand binding to CD44 also promotes fibrogenic, proliferative, and invasive phenotypes of HSCs. In HSCs, the interaction of low-MW HA with CD44 promotes HSC activation by upregulating profibrotic genes, metallopeptidase inhibitor 1, and pro-inflammatory genes such as Mcp-1 and C-X-C motif chemokine ligand 1 [87]. In addition, proteolytic cleavage of CD44 has been reported to occur during HSC activation [23,88].…”

Section: Cd44 Promotes Liver Fibrosismentioning

confidence: 99%

Current Evidence and Perspectives of Cluster of Differentiation 44 in the Liver’s Physiology and Pathology

Han,

Lee,

Jung

2024

IJMS

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Cluster of differentiation 44 (CD44), a multi-functional cell surface receptor, has several variants and is ubiquitously expressed in various cells and tissues. CD44 is well known for its function in cell adhesion and is also involved in diverse cellular responses, such as proliferation, migration, differentiation, and activation. To date, CD44 has been extensively studied in the field of cancer biology and has been proposed as a marker for cancer stem cells. Recently, growing evidence suggests that CD44 is also relevant in non-cancer diseases. In liver disease, it has been shown that CD44 expression is significantly elevated and associated with pathogenesis by impacting cellular responses, such as metabolism, proliferation, differentiation, and activation, in different cells. However, the mechanisms underlying CD44’s function in liver diseases other than liver cancer are still poorly understood. Hence, to help to expand our knowledge of the role of CD44 in liver disease and highlight the need for further research, this review provides evidence of CD44’s effects on liver physiology and its involvement in the pathogenesis of liver disease, excluding cancer. In addition, we discuss the potential role of CD44 as a key regulator of cell physiology.

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Hyaluronan in liver fibrosis: basic mechanisms, clinical implications, and therapeutic targets

Cited by 10 publications

References 83 publications

Implicating the cholecystokinin B receptor in liver stem cell oncogenesis

Implicating the cholecystokinin B receptor in liver stem cell oncogenesis

Elevated hyaluronic acid levels in severe SARS-CoV-2 infection in the post-COVID-19 era

Current Evidence and Perspectives of Cluster of Differentiation 44 in the Liver’s Physiology and Pathology

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