Loss of CEACAM1 in hepatocytes causes hepatic fibrosis

Sobia Zaidi; Suman Asalla; Harrison T Muturi; Lucia Russo; Raziyeh Abdolahipour; Getachew Debas Belew; Maria Benitez Iglesias; Mary Feraudo; Lensay Leon; Enoch Kuo; Xiuli Liu; Sivarajan Kumarasamy; Hilda E Ghadieh; Cara Gatto-Weis; Ali Zarrinpar; Sergio Duarte; Sonia M Najjar

doi:10.1111/eci.14177

Loss of CEACAM1 in hepatocytes causes hepatic fibrosis

Eur J Clin Invest. 2024 Feb 21:e14177. doi: 10.1111/eci.14177. Online ahead of print.

Authors

Sobia Zaidi¹, Suman Asalla¹, Harrison T Muturi¹, Lucia Russo², Raziyeh Abdolahipour¹, Getachew Debas Belew¹, Maria Benitez Iglesias¹, Mary Feraudo³, Lensay Leon³, Enoch Kuo⁴, Xiuli Liu⁵, Sivarajan Kumarasamy^{1

6}, Hilda E Ghadieh^{1

7}, Cara Gatto-Weis^{2

8}, Ali Zarrinpar³, Sergio Duarte³, Sonia M Najjar^{1

6}

Affiliations

¹ Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA.
² Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, USA.
³ Center for Diabetes and Endocrine Research (CeDER), College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, USA.
⁴ Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.
⁵ Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA.
⁶ Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA.
⁷ Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Balamand, Al-Koura, Lebanon.
⁸ Department of Pathology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, USA.

PMID: 38381498
DOI: 10.1111/eci.14177

Abstract

Background: The role of insulin resistance in hepatic fibrosis in Metabolic dysfunction-Associated SteatoHepatitis (MASH) remains unclear. Carcinoembryonic Antigen-related Cell Adhesion Molecule1 protein (CEACAM1) promotes insulin clearance to maintain insulin sensitivity and repress de novo lipogenesis, as bolstered by the development of insulin resistance and steatohepatitis in AlbuminCre + Cc1^fl/fl mice with liver-specific mouse gene encoding CEACAM1 protein (Ceacam1) deletion. We herein investigated whether these mice also developed hepatic fibrosis and whether hepatic CEACAM1 is reduced in patients with MASH at different fibrosis stages.

Methods: AlbuminCre + Cc1^fl/fl mice were fed a regular or a high-fat diet before their insulin metabolism and action were assessed during IPGTT, and their livers excised for histochemical, immunohistochemical and Western blot analysis. Sirius red staining was used to assess fibrosis, and media transfer was employed to examine whether mutant hepatocytes activated hepatic stellate cells (HSCs). Hepatic CEACAM1 protein levels in patients with varying disease stages were assessed by ELISA.

Results: Hepatocytic deletion of Ceacam1 caused hyperinsulinemia-driven insulin resistance emanating from reduced hepatic insulin clearance. AlbuminCre + Cc1^fl/fl livers showed inflammation, fibrosis and hepatic injury, with more advanced bridging and chicken-wire hepatic fibrosis under high-fat conditions. Media transferred from hepatocytes isolated from mutant mice activated control HSCs, likely owing to their elevated endothelin1 content. Interestingly, hepatic CEACAM1 levels were lower in the livers of patients with MASH and declined gradually with advanced fibrosis stage.

Conclusions: Hepatic CEACAM1 levels declined with progression of MASH in humans. The phenotype of AlbuminCre + Cc1^fl/fl mice assigned a key role to CEACAM1 loss from hepatocytes in hepatic fibrosis independently of other liver cells.

Keywords: fibrosis stage; hepatic stellate cells; insulin extraction; insulin resistance; steatohepatitis.

Abstract

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