Adipose-derived microRNA-518a drives hepatic cholesterol dysregulation and hypertension-related vascular remodeling in metabolic dysfunction-associated steatohepatitis via the MST1-AMPK-SREBP2 axis.

MST1 was identified as a key regulatory target of microRNA-518a in the context of MASH through integrative bioinformatic analyses.

• Identification involved Mendelian randomization and transcriptomic network analysis
• MST1 was selected as a candidate regulatory target from integrative bioinformatic approaches
• Findings were subsequently validated using human clinical samples, in vitro cell models, and a dietary mouse model of MASH

Increased microRNA-518a expression suppressed MST1, leading to reduced AMPK activation and enhanced SREBP2-mediated cholesterol biosynthesis.

• The pathway described is microRNA-518a → suppression of MST1 → reduced AMPK activation → enhanced SREBP2-mediated cholesterol biosynthesis
• This axis represents a mechanistic link between adipose-derived microRNA signaling and hepatic cholesterol dysregulation
• Functional validation was conducted in vitro using cell models

MicroRNA-518a promoted hepatic cholesterol accumulation, lipid deposition, inflammation, and fibrotic changes in experimental models.

• Functional experiments demonstrated these effects in vitro and in a dietary mouse model of MASH
• Effects included cholesterol accumulation, lipid deposition, inflammation, and fibrotic changes
• Restoration of MST1 partially reversed these pathological effects

Restoration of MST1 expression partially reversed the hepatic metabolic and pathological effects induced by microRNA-518a.

• MST1 restoration was used as a functional rescue experiment
• Partial reversal was observed for cholesterol accumulation, lipid deposition, inflammation, and fibrotic changes
• This finding supports MST1 as a functionally relevant downstream target of microRNA-518a in the MASH context

Exosome-mediated delivery of microRNA-518a modulated hepatic metabolic responses through intercellular communication.

• Exosome-mediated microRNA delivery was used as a functional validation approach
• Results supported microRNA-518a's ability to act as an inter-organ communicator between adipose tissue and the liver
• This positions microRNA-518a as an adipose tissue-derived mediator capable of affecting distal hepatic metabolism

The MST1-AMPK-SREBP2 axis identified in MASH converges with vascular regulatory networks, suggesting mechanistic links to hypertension and arterial stiffness.

• The study identified overlap between the MST1-AMPK-SREBP2 signaling pathway and vascular regulatory networks
• This convergence suggests shared pathophysiological mechanisms underlying the frequent co-occurrence of MASH with hypertension and systemic vascular remodeling
• The authors note 'broader implications for understanding the metabolic-vascular comorbidities frequently observed in MASH patients, including hypertension and arterial stiffness'

Mendelian randomization analysis was employed to identify candidate regulatory pathways associated with MASH, supporting a causal inference approach.

• Mendelian randomization was combined with transcriptomic network analysis in the bioinformatic discovery phase
• This approach was used to prioritize regulatory pathways before functional validation
• Human clinical samples were included in the validation pipeline alongside in vitro and in vivo models