Lipid-Induced Endothelial Vascular Cell Adhesion Molecule 1 Promotes Nonalcoholic Steatohepatitis Pathogenesis

Open chromatin landscape profiling combined with genome-wide transcriptome analysis showed robust transcriptional upregulation of liver sinusoidal endothelial cells-vascular cell adhesion molecule 1 in murine nonalcoholic steatohepatitis.
[Journal of Clinical Investigation]
Furuta, K., Guo, Q., Pavelko, K. D., Lee, J.-H., Robertson, K. D., Nakao, Y., Melek, J., Shah, V. H., Hirsova, P., & Ibrahim, S. H. (2021). Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis. The Journal of Clinical Investigation. https://doi.org/10.1172/JCI143690 Cite
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LECT2 as a Hepatokine Links Liver Steatosis to Inflammation via Activating Tissue Macrophages in NASH

Hepatic expression of leukocyte cell-derived chemotaxin 2 (LECT2) was upregulated in association with the inflammatory signature in human liver tissues. The elevation of LECT2 shifted liver residual macrophage to the M1-like phenotype, and contributed to the development of liver inflammation.
[Scientific Reports]
Takata, N., Ishii, K., Takayama, H., Nagashimada, M., Kamoshita, K., Tanaka, T., Kikuchi, A., Takeshita, Y., Matsumoto, Y., Ota, T., Yamamoto, Y., Yamagoe, S., Seki, A., Sakai, Y., Kaneko, S., & Takamura, T. (2021). LECT2 as a hepatokine links liver steatosis to inflammation via activating tissue macrophages in NASH. Scientific Reports, 11(1), 555. https://doi.org/10.1038/s41598-020-80689-0 Cite
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Metacrine Initiates Phase IIa Combination Trial of MET409 with Empagliflozin in Patients with Type II Diabetes and NASH

Metacrine, Inc. announced that the first patient has been treated in the company’s Phase IIa trial evaluating MET409 in combination with empagliflozin, a sodium-glucose cotransport-2 inhibitor, in patients with both type II diabetes mellitus and nonalcoholic steatohepatitis.
[Metacrine, Inc.]
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Iron-Rich Kupffer Cells Exhibit Phenotypic Changes during the Development of Liver Fibrosis in NASH

The authors reported a unique histological structure termed “crown-like structure”, where liver-resident macrophages surrounded dead hepatocytes, scavenged their debris, and induced inflammation and fibrosis in nonalcoholic steatohepatitis (NASH).
[iScience]
Kanamori, Y., Tanaka, M., Itoh, M., Ochi, K., Ito, A., Hidaka, I., Sakaida, I., Ogawa, Y., & Suganami, T. (2021). Iron-Rich Kupffer Cells Exhibit Phenotypic Changes during the Development of Liver Fibrosis in NASH. IScience, 0(0). https://doi.org/10.1016/j.isci.2020.102032 Cite
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Metacrine Reports Positive Results from Phase I Trial of MET642

Metacrine, Inc. has reported preliminary results from its Phase I trial of MET642, a farnesoid X receptor (FXR) agonist being developed for the treatment of non-alcoholic steatohepatitis and inflammatory bowel disease. Findings show that treatment with MET642 was safe and generally well-tolerated and demonstrated a sustained pharmacokinetic profile and robust FXR target engagement after 14 days of daily oral dosing in healthy volunteers.
[Metacrine, Inc.]
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A Human Pluripotent Stem Cell Model for the Analysis of Metabolic Dysfunction in Hepatic Steatosis

Scientists present a human PSC-derived model of hepatic steatosis, which overcomes inherent challenges of current models, and provides insights into the metabolic rewiring associated with steatosis.
[iScience]
Sinton, M. C., Meseguer-Ripolles, J., Lucendo-Villarin, B., Wernig-Zorc, S., Thomson, J. P., Carter, R. N., Lyall, M. J., Walker, P. D., Thakker, A., Meehan, R. R., Lavery, G. G., Morton, N. M., Ludwig, C., Tennant, D. A., Hay, D. C., & Drake, A. J. (2020). A human pluripotent stem cell model for the analysis of metabolic dysfunction in hepatic steatosis. IScience, 0(0). https://doi.org/10.1016/j.isci.2020.101931 Cite
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Altimmune Commences Dosing in Phase I Clinical Trial of ALT-801, a Long-Acting GLP-1/Glucagon Receptor Dual Agonist for the Treatment of NASH

Altimmune, Inc. announced that it has commenced dosing in a Phase I single ascending dose and multiple ascending dose clinical study of ALT-801. ALT-801 is a long-acting GLP-1/glucagon receptor dual agonist being developed for the treatment of non-alcoholic steatohepatitis (NASH), which is expected to affect more than 13 million adults in the United States.
[Altimmune, Inc.]
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Stress Can Attenuate Hepatic Lipid Accumulation via Elevation of Hepatic β-Muricholic Acid Levels in Mice with Nonalcoholic Steatohepatitis

βMCA suppressed lipid accumulation in mouse primary hepatocytes exposed to palmitic acid/oleic acid, but cholic acid did not. In addition, Cyp7a1 expression seemed to be related to lipid accumulation in hepatocytes.
[Laboratory Investigation]
Takada, S., Matsubara, T., Fujii, H., Sato-Matsubara, M., Daikoku, A., Odagiri, N., Amano-Teranishi, Y., Kawada, N., & Ikeda, K. (2020). Stress can attenuate hepatic lipid accumulation via elevation of hepatic β-muricholic acid levels in mice with nonalcoholic steatohepatitis. Laboratory Investigation, 1–11. https://doi.org/10.1038/s41374-020-00509-x Cite
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Response to Iron Overload in Cultured Hepatocytes

Expression levels of molecules involved in cellular signaling such as AMPK pathway, TGF-β family pathway, and MAP kinase pathway were decreased by FeCl3 treatment in rat primary hepatocytes. Cell viability in response to FeCl3 treatment was decreased in RPH but not in HepG2 and Hepa1-6 cells.
[Scientific Reports]
Chen, H.-J., Sugiyama, M., Shimokawa, F., Murakami, M., Hashimoto, O., Matsui, T., & Funaba, M. (2020). Response to iron overload in cultured hepatocytes. Scientific Reports, 10(1), 21184. https://doi.org/10.1038/s41598-020-78026-6 Cite
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CytoDyn Announces First Patient Enrolled in Phase II Trial for NASH

CytoDyn, Inc. announced the first patient first visit metric was met for the company’s Phase II clinical trial for the treatment of nonalcoholic steatohepatitis (NASH). The Phase II trial is designed to test whether leronlimab may inhibit the devastating liver fibrosis associated with NASH.
[CytoDyn, Inc.]
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Immunological Mechanisms and Therapeutic Targets of Fatty Liver Diseases

Scientists review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of alcoholic liver disease and nonalcoholic fatty liver disease. Multiple cell types in the liver, including macrophages, neutrophils, other immune cell types and hepatocytes, are involved in fatty liver disease inflammation.
[Cellular & Molecular Immunology]
Wang, H., Mehal, W., Nagy, L. E., & Rotman, Y. (2020). Immunological mechanisms and therapeutic targets of fatty liver diseases. Cellular & Molecular Immunology, 1–19. https://doi.org/10.1038/s41423-020-00579-3 Cite
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