AKAP12 ameliorates liver injury via targeting PI3K/AKT/PCSK6 pathway

Xuan Wu; Yuhong Luo; Shan Wang; Yueying Li; Meiyu Bao; Yuanjiang Shang; Lei Chen; Weiwei Liu

doi:10.1016/j.redox.2022.102328

AKAP12 ameliorates liver injury via targeting PI3K/AKT/PCSK6 pathway

Redox Biol. 2022 Jul:53:102328. doi: 10.1016/j.redox.2022.102328. Epub 2022 May 6.

Authors

Xuan Wu¹, Yuhong Luo², Shan Wang³, Yueying Li⁴, Meiyu Bao⁴, Yuanjiang Shang⁴, Lei Chen⁵, Weiwei Liu⁶

Affiliations

¹ Department of Laboratory Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China; Central Laboratory and Department of Laboratory Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200070, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, China.
² Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
³ International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, China; Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
⁴ Central Laboratory and Department of Laboratory Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200070, China.
⁵ International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, China. Electronic address: chenlei@smmu.edu.cn.
⁶ Department of Laboratory Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China; Central Laboratory and Department of Laboratory Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200070, China. Electronic address: weiweiliu@shutcm.edu.cn.

Abstract

A kinase anchor protein 12（AKAP12）is a scaffold protein that is critical for cell structure maintenance and signal transduction. However, the role of AKAP12 in liver injury remains unclear. Here, we attempt to explore the potential contribution of AKAP12 in liver injury and elucidate its underlying molecular mechanism. We found that AKAP12 deletion in acute liver injury (ALI) activates the PI3K/AKT phosphorylation signaling pathway, induces the increased expression of PCSK6 and its downstream inflammation-related genes, and prompts macrophages to produce a large number of inflammatory factors. And knockdown of PCSK6 by in vivo siRNA assay reversed in liver injury AKAP12^Δhep mice, demonstrating that PCSK6 has an important role in ALI. Furthermore, we found that signal transducer and activator of transcription 3 (STAT3) and serine/threonine kinase Akt (AKT) were upregulated in AKAP12^Δhep mice of chronic liver injury. To sum up, our study here demonstrates that AKAP12 has a protective role in ALI and chronic liver fibrosis, at least in part through inhibition of the PI3K/AKT/PCSK6 pathway. Our findings provide a new potential treatment for liver injury with important clinical implications.

Keywords: AKAP12; Inflammatory factor; Liver injury; Macrophage infiltration; PCSK6.

MeSH terms

A Kinase Anchor Proteins* / genetics
A Kinase Anchor Proteins* / metabolism
Animals
Cell Cycle Proteins* / metabolism
Fibrosis
Liver / metabolism
Mice
Phosphatidylinositol 3-Kinases* / genetics
Phosphatidylinositol 3-Kinases* / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction

Substances

A Kinase Anchor Proteins
Akap12 protein, mouse
Cell Cycle Proteins
Proto-Oncogene Proteins c-akt