Hepatocyte SLCO4C1 is a cAMP uptake transporter for inhibiting lipogenesis and a therapeutic target for MASLD
Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent cause of chronic liver disease worldwide, currently lacks precision medicine treatments. SLCO4C1 acts as a transporter for endogenous compounds and xenobiotics. This study aims to investigate whether SLCO4C1 plays a regulatory role in MASLD pathogenesis and to elucidate the underlying mechanisms. Using human, mouse and cellular models, we found that hepatocyte SLCO4C1 is upregulated in MASLD patients, where it serves as a key cAMP transporter dependent on Gln463, suppressing lipogenesis through the PKA-CREB-SREBP1 pathway. Hepatocyte-specific delivery of Slco4c1 via AAV8-TBG increased hepatic cAMP levels, alleviating steatosis, inflammation, and fibrosis in MASLD male mice. Similarly, forskolin, an adenylyl cyclase activator that elevates cAMP, alleviated MASLD progression, underscoring the translational potential of targeting the SLCO4C1-cAMP signaling axis. Mechanistically, during MASLD progression, FGF21 upregulates hepatic Slco4c1 expression through activating ERK/MAPK signaling, which induces EGR1 to directly bind the Slco4c1 promoter, increasing intrahepatic cAMP levels.
Authors
- Changpei Gan (ORCID: https://orcid.org/0000-0003-2601-557X)
- Xinshou Ouyang (ORCID: https://orcid.org/0000-0003-3423-0042)
- Yangyang Li (ORCID: https://orcid.org/0000-0003-1085-677X)
- Minghua Zheng
- Lei Zuo (ORCID: https://orcid.org/0000-0001-7039-1025)
- Xin Xie
- Liangjun Zhang (ORCID: https://orcid.org/0000-0002-7053-8661)
- Jiangchuan Tian
- Siyi Jiang
- Xiaolei Hu
- Huayu Zhang
- Christopher D. Byme
- Mindian Li
- Ling Li
- Nan Zhao
- Xiaojia Huang
- Chuanzheng Sun
- Zhixian Zhu
- Huaizheng Liu
- Ying Cheng
- Xiaoxun Zhang
- Qian Yuan
- Xiaolan Yang
- Jingjing Ding
- Jingdong Zhao
- Jin Chai
- Sen Liang
- Qiong Pan
- Giovanni Targher
Institutions
- Central South University (CN)
- Army Medical University (CN)
- Wenzhou Medical University (CN)
- Southampton General Hospital (GB)
- First Affiliated Hospital of Wenzhou Medical University (CN)
- University Hospital Southampton NHS Foundation Trust (GB)
- Yale University (US)
- Ospedale Sacro Cuore Don Calabria (IT)
- Southwest Hospital (CN)
- Guang’anmen Hospital (CN)
- Third Xiangya Hospital (CN)
- University of Southampton (GB)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-13
- DOI
- https://doi.org/10.1038/s41467-026-70729-0
- Primary Topic
- Drug Transport and Resistance Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Chongqing Postdoctoral Science Foundation
- National Natural Science Foundation of China
- Army Medical University
- Centre Scientifique et Technique du Bâtiment
- National Science and Technology Major Project