De Luca, F. | Search bioRxiv

bioRxiv2025

Dyslipidemic SPTLC3 Integrates Bile Acid-FXR Signaling with Sphingolipid Remodeling in MASLD

Molecular mechanisms driving metabolic disease pathogenesis remain poorly understood. Genetic and functional studies implicate SPTLC3 with dyslipidemia. SPTLC3 synthesizes atypical long-chain bases (LCB) precursors for sphingolipid production. We demonstrate significant SPTLC3 expression in human liver. ORMDL1-3 regulate SPTLC3 post-translationally in hepatic and non-hepatic cells. Independently, farnesoid X receptor (FXR) represses hepatic SPTLC3 transcription via a negative promoter element. In mice, high-fat diet (HFD) induced whereas bile acids normalized hepatic SPTLC3 transcription. SPTLC3 derived LCBs in plasma originate from the liver and are elevated in HFD-fed mice and in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Cross-species comparison revealed marked differences in LCB composition between mice and humans. Notably, omega-3-methylsphingosine (meC18SO) was significantly associated with MASLD in humans but undetectable in mice. In Huh7 cells, meC18SO enhanced complex II and IV activity, oxygen consumption, and mitochondrial ROS content. FXR-SPTLC3 axis and presented findings have potential implications for future translational research.

biochemistry↗

bioRxiv2021

The role of ventromedial prefrontal cortex in reward valuation and future thinking during intertemporal choice

Intertemporal choices require trade-offs between short-term and long-term outcomes. Ventromedial prefrontal cortex (vmPFC) damage causes steep discounting of future rewards (delay discounting; DD) and impoverished episodic future thinking (EFT). The role of vmPFC in reward valuation, EFT, and their interaction during intertemporal choice is still unclear. Here, twelve patients with lesions to vmPFC and forty-one healthy controls chose between smaller-immediate and larger-delayed hypothetical monetary rewards while we manipulated reward magnitude and the availability of EFT cues. In the EFT condition, participants imagined personal events to occur at the delays associated with the larger-delayed rewards. We found that DD was steeper in vmPFC patients compared to controls, and not modulated by reward magnitude. However, EFT cues downregulated DD in vmPFC patients as well as controls. These findings indicate that vmPFC integrity is critical for the valuation of (future) rewards, but not to instill EFT in intertemporal choice.

neuroscience↗