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Asprosin-FABP5 Interaction Modulates Mitochondrial Fatty Acid Oxidation through PPARα Contributing to MASLD
Yuan-Yuan Yu1, Min Feng1, Yi Chen1
1Department of Pharmacology, SKLFZCD, (State Key Laboratory -Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
Abstract:
Alterations in liver metabolism play a pivotal role in the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Asprosin is reported to be released from white adipose tissue during fasting and targets the liver. However, the role of asprosin, especially from organs other than adipose tissue, in MASLD remains poorly understood. These findings demonstrate that plasma asprosin levels are significantly elevated in MASLD patients and animal models. Additionally, asprosin expression increased in the liver of MASLD mice. Hepatocyte-specific overexpression of asprosin impairs mitochondrial fatty acid β-oxidation (FAO), whereas its knockdown not only enhances FAO in mice but also compensates for fenofibrate's limitations in MASLD treatment. Mechanistic investigations reveal that the interaction of asprosin with FABP5 facilitates its abnormal nuclear localization, and asprosin directly bound to and inhibites peroxisome proliferator-activated receptor elements (PPREs), which negatively regulated PPARα transcriptional activity, and disrupts hepatic FAO pathways. GalNAc-siRNAs targeting hepatic FABP5 ameliorate hepatic steatosis. These findings reveal that the secretory adipose factor asprosin is expected to act as a biological marker for early clinical diagnosis and prognostic evaluation of MASLD. Moreover, targeting hepatic asprosin gene inhibition and GalNAc-siRNAs to inhibit hepatic FABP5 both offer potential therapeutic benefits in the treatment of MASLD.
Insights
Asprosin, a fasting-induced hormone, is elevated in metabolic dysfunction-associated steatotic liver disease (MASLD) and impairs liver fatty acid oxidation. Targeting asprosin or FABP5 offers potential MASLD therapies.
Area of Science:
- Hepatology
- Metabolic Diseases
- Molecular Biology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) involves complex liver metabolic alterations.
- Asprosin, a fasting-released hormone, targets the liver, but its role in MASLD is unclear.
Purpose of the Study:
- To investigate the role of asprosin in MASLD pathogenesis.
- To explore asprosin as a potential biomarker and therapeutic target for MASLD.
Main Methods:
- Measured plasma asprosin levels in MASLD patients and animal models.
- Utilized hepatocyte-specific asprosin overexpression and knockdown models in mice.
- Investigated molecular mechanisms involving FABP5, PPARα, and fatty acid oxidation (FAO).
- Assessed therapeutic potential of GalNAc-siRNAs targeting FABP5.
Main Results:
- Plasma asprosin levels and hepatic asprosin expression are elevated in MASLD.
- Hepatocyte asprosin overexpression impairs hepatic FAO; knockdown enhances FAO and improves MASLD treatment outcomes.
- Asprosin interacts with FABP5, leading to abnormal nuclear localization and inhibition of PPARα transcriptional activity, disrupting hepatic FAO.
- Targeting hepatic FABP5 with GalNAc-siRNAs ameliorates hepatic steatosis.
Conclusions:
- Elevated asprosin is implicated in MASLD pathogenesis by disrupting hepatic FAO.
- Asprosin serves as a potential biomarker for MASLD diagnosis and prognosis.
- Inhibiting hepatic asprosin or FABP5 presents promising therapeutic strategies for MASLD.
