Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
Brian A. Fellenstein
Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
James Ahodantin
Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC USA; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
Andre J. Jeyarajan
Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
Yongtao Wang
Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
Sanjoy K. Khan
Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
Min Xu
Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
Wenyu Lin
Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
Nadia Alatrakchi
Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
Lishan Su
Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC USA; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
Raymond T. Chung
Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA; Corresponding authors. Address: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA.
Shadi Salloum
Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA; Corresponding authors. Address: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA.
Background & Aims: HIV accelerates liver fibrosis attributable to multiple etiologies, including HCV, HBV, and steatotic liver disease. Evidence also suggests that HIV infection itself is associated with liver fibrogenesis. Recent studies have implicated Yes-associated protein 1 (YAP1) and the upstream lysophosphatidic acid (LPA)/PI3K/AKT pathway as critical regulators of hepatic fibrogenesis, and suggest a connection to HIV-related liver fibrosis. However, the relationship between YAP/PI3K/AKT pathway activation and HIV-related liver fibrosis remains uncertain. Methods: qPCR, western blot, immunofluorescence, and ELISA (replicates n ≥3) were performed in an unbiased humanized mouse model (NRG-hu HSC mice, n = 6), the precision cut liver slice ex vivo model, and both traditional in vitro models as well as a 3D spheroid system. Results: YAP target gene mRNA and protein levels (ANKRD, CTGF, CYR61) were upregulated across all models exposed to HIV. Humanized mice infected with HIV had significant increases in the percentage of YAP-positive nuclei (2.2-fold) and the percentage area of Sirius Red collagen staining (3.3-fold) compared to control mice. Serum concentrations of LPA were increased 5.8-fold in people living with HIV compared to healthy controls. Modulation of LPAR1, PI3K, and AKT by either inhibitors or small-interfering RNAs abrogated the fibrotic effects of HIV exposure and downregulated YAP target genes within cultured liver cells. Conclusions: The LPAR/PI3K/AKT axis is vital for the activation of YAP and hepatic fibrogenesis due to HIV infection. This novel mechanistic insight suggests new pharmacologic targets for treatment of liver fibrosis in people living with HIV. Impact and implications:: There are currently no FDA-approved treatments for cirrhosis, while liver disease is the second leading cause of mortality among people living with HIV after AIDS. Increased lysophosphatidic acid concentrations and AKT activation after HIV infection found in recent work suggest that the Hippo pathway may be a key regulator of HIV-related fibrogenesis. By linking lysophosphatidic acid signaling, YAP activation, and HIV-related fibrogenesis, this mechanism presents a target for future research into therapeutic interventions for not only HIV but also other liver diseases, e.g. metabolic dysfunction- or alcohol-associated liver disease.
