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RNF128 regulates the adaptive metabolic response to fasting by modulating PPARα function
Yu-Lung Lin1,2, Pei-Yao Liu3,4, Yu-Ling Tsai5,6
1The Ph.D. Program for Translational Medicine, College for Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Cell Death and Differentiation
|September 10, 2025
Summary
Researchers discovered that RING finger protein 128 (RNF128) degrades the transcription factor PPARα during fasting. This RNF128-mediated degradation is crucial for metabolic adaptation and lipid regulation in the liver.
Area of Science:
- Metabolic regulation
- Molecular biology
- Lipid metabolism
Background:
- Peroxisome proliferator-activated receptor alpha (PPARα) regulates key metabolic processes like fatty acid oxidation and ketogenesis during fasting.
- The precise molecular mechanisms governing PPARα activity, particularly its regulation during nutrient deprivation, are not fully understood.
Purpose of the Study:
- To identify novel regulators of PPARα function during fasting.
- To elucidate the role of RING finger protein 128 (RNF128) in PPARα-mediated metabolic adaptation.
Main Methods:
- * In vitro studies: Investigated the interaction between RNF128 and PPARα, assessing polyubiquitination and degradation of PPARα.
- * Gene expression analysis: Measured the impact of RNF128 on PPARα target genes, including fibroblast growth factor 21 (FGF21) and lipid metabolism-related genes.
- * In vivo studies: Utilized RNF128-deficient mice and adeno-associated virus (AAV) serotype 8 mediated overexpression models to assess metabolic parameters during fasting.
Main Results:
- * Identified RNF128 as a novel PPARα-binding protein that promotes PPARα polyubiquitination and subsequent degradation.
- * RNF128 overexpression suppressed PPARα activity, inhibiting FGF21 expression and lipid metabolism genes during fasting.
- * Silencing RNF128 enhanced PPARα-dependent fatty acid oxidation and ketogenesis in starved cells.
- * In vivo, RNF128 deficiency improved lipid profiles and boosted fatty acid oxidation and ketogenesis during fasting.
- * AAV8-mediated RNF128 overexpression in mice led to elevated lipid levels and reduced expression of metabolic genes.
Conclusions:
- RNF128 acts as a critical negative regulator of PPARα during fasting by promoting its degradation.
- RNF128 plays a vital role in hepatic metabolic adaptation to nutrient deprivation by modulating PPARα activity.
- RNF128 represents a potential therapeutic target for metabolic disorders associated with impaired fasting response.
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