2. Academic Validation
  3. Isoform specific regulation of osteopontin by AKT2 in hepatocytes and livers

Isoform specific regulation of osteopontin by AKT2 in hepatocytes and livers

  • Cell Signal. 2025 Aug:132:111799. doi: 10.1016/j.cellsig.2025.111799.
Ielyzaveta Slarve 1,  Yushan Wang 1,  Yining Ding 1,  Xiaoteng Niu 1,  Qi Tang 1,  Chengyou Jia 2,  Taojian Tu 1,  Handan Hong 1,  Guo Zhang 1,  Yiwei Gu 1,  Zifei Xu 1,  Samantha Skinner 1,  Lina He 1,  Brittney Hua 1,  Phillip Nguyen 1,  Yiren Zhou 1,  Lulu Chen 1,  Karam Ashouri 3,  Anastasia Martynova 3,  Christina Nakhoul 3,  Ali Rastegarpour 3,  Houda Alachkar 4,  Heinz-Josef Lenz 3,  Anthony El-Khoueiry 3,  Linda Sher 5,  Shefali Chopra 5,  Liyun Yuan 5,  Bangyan Li Stiles 6
Affiliations

Affiliations

  • 1 Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA.
  • 2 Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA; Department of Nuclear Medicine, Central Laboratory for Medical Research, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
  • 3 Division of Medical Oncology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.
  • 4 Department of Clinical Pharmacy, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
  • 5 Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • 6 Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: bstiles@usc.edu.
PMID: 40216173 DOI: 10.1016/j.cellsig.2025.111799
Abstract

Elevated levels of Osteopontin (OPN), an inflammatory cytokine, are correlated with chronic inflammatory conditions and liver Cancer. In this study, we explored the regulation of OPN in liver and hepatocytes by Akt1 vs. Akt2, the two Akt isoforms expressed in hepatocytes and livers. Using a mouse model lacking PTEN (Phosphatase and tensin homologue deleted on chromosome 10), the negative regulator of phosphatidylinositol 3-kinase (PI3K)/Akt signaling, expression of secreted phosphoprotein 1 (Spp1), the gene encoding OPN, was found to be the topmost significantly upregulated gene in the liver. Using an add-back experiment in hepatocytes isolated from these mice, we show that PTEN regulates the expression of Spp1 mRNA as well as OPN protein levels. Exploring how PTEN regulates the expression of Spp1/OPN, we investigated the differential roles of Akt1 vs. Akt2 using hepatocytes isolated from mice lacking each Akt isoform in the liver. We showed here that levels of Spp1/OPN in hepatocytes are lost with deletion of Akt2 but not Akt1. Deletion of Akt2 significantly attenuated both basal expression of OPN and its response to IGF-1 stimulation. Akt1 loss, on the Other hand, permitted more robust induction of OPN by IGF-1 stimulation. Furthermore, mice lacking Akt2 and PTEN exhibit significantly lower OPN expression in the liver. Together, this study showed that OPN levels are regulated by the PI3K/Akt signal in hepatocytes and that Akt2 but not Akt1 is responsible for its induction in response to stimulation of the PI3K signaling pathway.

Keywords

AKT1; AKT2; Liver Cancer; MAFLD; OPN; Osteopontin; PI3K; PTEN; Spp1; Steatosis.

Figures
Products
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    Product Name
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    Target
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  • HY-15244
    99.95%, PI3Kα Inhibitor