Selenoprotein H Functions as a PPARα Coactivator to Link Selenium Homeostasis to Hepatic Lipid Metabolism and Protect against Steatohepatitis
Source abstract
Abstract
ABSTRACT Selenium is an essential trace element whose dysregulation is associated with diverse disease risks; however, its specific role in hepatic metabolism remains poorly defined. Here we delineate a novel selenium‐selenoprotein H (SELENOH)‐PPARα signaling axis that is critical for hepatic lipid homeostasis. We first uncovered a global impairment of selenoprotein translation as a key feature of metabolic dysfunction‐associated steatohepatitis (MASH) in human patients and mouse models. Both dietary selenium supplementation and genetically rescuing selenoprotein biosynthesis attenuated MASH pathology, establishing a causal link. Through a targeted screen, we pinpointed SELENOH as the key hepatoprotective selenoprotein governing hepatic fatty acid oxidation (FAO). Diverging from the canonical redox functions of selenoproteins, SELENOH operates as a scaffolding coactivator for the nuclear receptor PPARα. SELENOH binds to ligand‐activated PPARα and orchestrates the assembly and chromatin recruitment of the PPARα‐P300 transactivation complex to drive FAO gene expression. This nexus is disrupted in MASH livers due to SELENOH deficiency but is reconstituted by selenium supplementation. These findings altogether define selenium homeostasis as a fundamental regulator of nuclear receptor function and unveil promising therapeutic avenues for MASH.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Selenium in Biological Systems · Sulfur Compounds in Biology · Paraoxonase enzyme and polymorphisms
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences P. R. China
Department of Pathology Linyi People's Hospital Shandong China
Jinan Microecological Biomedicine Shandong Laboratory Jinan China
Department of Gastrointestinal Surgery Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University The Third Affiliated Hospital of Nanjing Medical University Changzhou Medical Center Nanjing Medical University Changzhou China
Division of Hepatobiliary and Transplantation Surgery Department of General Surgery Nanjing Drum Tower Hospital the Affiliated Hospital of Medical School Nanjing University Nanjing China
Department of Hepatobiliary and Pancreatic Surgery The Second Affiliated Hospital of Fujian Medical University Quanzhou Fujian China
Department of Laboratory Medicine Linyi People's Hospital Shandong China
Shanghai Key Laboratory of Reproductive Medicine Shanghai China
Funding
National Key Research and Development Program of China · National Natural Science Foundation of China · China Postdoctoral Science Foundation
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