Divergent regulation of cellular cholesterol metabolism by seaweed-derived fucosterol and saringosterol

Monique Mulder^1*Na Zhan^2,3,4,5Nikita Martens^1,6Yanlin Li¹Gardi Voortman¹Frank Leijten¹Silvia Friedrichs⁴Martien P.M. Caspers^4,7Lars Verschuren⁷Tim Vanmierlo^6,8,9Marieke Smit¹⁰Folkert Kuipers¹⁰Johan W. Jonker¹⁰Vincent W. Bloks¹⁰Marcella Palumbo¹¹Francesca Zimetti¹¹Maria Pia Adorni¹¹Hongbing Liu^3*Dieter Lütjohann^4*

• ¹Internal Medicine, Erasmus University Rotterdam, Rotterdam, Netherlands
• ²Erasmus Universiteit Rotterdam, Rotterdam, Netherlands
• ³Ocean University of China, Qingdao, China
• ⁴Universitatsklinikum Bonn, Bonn, Germany
• ⁵Guangzhou Medical University, Guangzhou, China
• ⁶Universiteit Hasselt, Hasselt, Belgium
• ⁷TNO, The Hague, Netherlands
• ⁸Erasmus MC, Rotterdam, Netherlands
• ⁹Universiteit Maastricht, Maastricht, Netherlands
• ¹⁰Universitair Medisch Centrum Groningen, Groningen, Netherlands
• ¹¹Universita degli Studi di Parma, Parma, Italy

Marine sterols derived from brown seaweeds, particularly fucosterol and its oxidized derivative, saringosterol, show promise as therapeutic candidates for Alzheimer's disease (AD) and cardiovascular diseases. Here, we aimed to explore mechanisms underlying their beneficial effects observed in disease-related in animal models. Both fucosterol and saringosterol were internalized by HepG2 and CCF-STTG1 cells and activated nuclear Liver X Receptors (LXRα and LXRβ), key regulators of lipid metabolism and inflammation. Fucosterol induced cholesterol synthesis and increased intracellular desmosterol, an endogenous LXR agonist with anti-inflammatory properties. In contrast, saringosterol reduced both cholesterol synthesis and intracellular desmosterol. Yet, only saringosterol reduced the Lipopolysaccharide (LPS)-induced Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-α production in THP-1-derived macrophages, indicating anti-inflammatory properties, while both sterols enhanced cholesterol efflux. Administration of a fucosterol-enriched diet (0.2% w/w for 1 week) to wild-type mice increased hepatic desmosterol (+40%) and decreased 5α-cholestanol contents. Serum 7α-hydroxycholesterol, and 27-hydroxycholesterolwere decreased. Diet supplementation with saringosterol (0.02% w/w for 1 week) also increased hepatic desmosterol (+44%), as well as 7α-hydroxycholesterol in liver and brain, and 27-hydroxycholesterol in serum. Transcriptome analysis of the hippocampus showed that fucosterol mainly affected synaptic signaling and hormonal pathways linked to neuronal plasticity, while saringosterol primarily modulated protein quality control and neurodegenerative pathways. These findings demonstrate that both fucosterol and saringosterol activate LXRs but via different modes of action. This work is the first to directly compare the cellular and in vivo effects of fucosterol and saringosterol, revealing shared LXR activation but divergent impacts on hepatic, brain and systemic cholesterol metabolism and expression of genes involved in neural pathways, indicating complementary neuroprotective effects with therapeutic potential for AD and related disorders.