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Published on: September 12, 2019
YAP mediates HIV-related liver fibrosis
Volney A Spalding1, Brian A Fellenstein1, James Ahodantin2,3
1Liver 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.
Insights
HIV accelerates liver fibrosis by activating the YAP/PI3K/AKT pathway. Targeting this pathway offers new therapeutic strategies for liver disease in people living with HIV.
Area of Science:
- Hepatology
- Virology
- Molecular Biology
Background:
- HIV infection accelerates liver fibrosis from various causes.
- HIV itself may promote liver fibrogenesis.
- The YAP1 and LPA/PI3K/AKT pathway are implicated in liver fibrosis.
Purpose of the Study:
- To investigate the role of the YAP/PI3K/AKT pathway in HIV-related liver fibrosis.
- To explore potential therapeutic targets for HIV-associated liver disease.
Main Methods:
- Utilized humanized mouse models, precision cut liver slices, and in vitro models.
- Employed qPCR, western blot, immunofluorescence, and ELISA.
- Investigated YAP target gene expression and protein levels.
Main Results:
- HIV exposure upregulated YAP target genes (ANKRD, CTGF, CYR61) across models.
- HIV-infected mice showed increased YAP-positive nuclei and collagen deposition.
- Increased serum lysophosphatidic acid (LPA) in people with HIV was observed.
Conclusions:
- The LPAR/PI3K/AKT axis is crucial for YAP activation and HIV-induced liver fibrogenesis.
- This pathway represents a novel therapeutic target for liver fibrosis in people with HIV.
