Intestinal lipid absorption, the entry point for fats into the body, requires the coordinated actions of bile acids and lipases. Here, we uncover distinct yet cooperative roles of bile acids in driving the differential uptake of dietary fatty acids. We first decreased the bile acid pool size by disrupting the rate-limiting enzyme in bile acid synthesis, Cyp7a1, using liver-directed gene editing in mice. Compared with lipase inhibition, reduced bile acids prevented diet-induced obesity, increased anorectic hormones, suppressed excessive eating, and improved systemic lipid metabolism. Remarkably, decreasing bile acids selectively reduced the absorption of saturated fatty acids but preserved polyunsaturated fatty acids. By targeting additional bile acid enzymes, we identified specific functions of individual bile acid species. Mechanistically, we show that cholic acid preferentially solubilizes polyunsaturated fatty acids into mixed micelles for intestinal uptake. Our studies demonstrate that bile acids can selectively control fatty acid uptake, revealing insights for future interventions in metabolic diseases.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

Untargeted metabolomics is a powerful tool for detecting perturbations in biological systems, offering significant potential for screening for rare inherited metabolic disorders (IMDs). However, the rarity and vast diversity of these diseases, results in limited availability of samples and incomplete metabolic pathway knowledge for each condition. Current diagnostic procedures rely heavily on manual interpretation, which is time-consuming, and data driven approaches are insufficient for small sample sizes.
To develop a diagnostic algorithm for IMDs addressing the challenges posed by small sample sizes and continuously evolving datasets.
77 IMD patients (35 different IMDs) and 136 control samples were collected from Copenhagen University Hospital, Rigshospitalet. The metabolome was analyzed using liquid chromatography-mass spectrometry. An algorithm partially based on sparse hierarchical clustering was designed to generate IMD-specific metabolic signatures from metabolomics data, enabling comparison with undiagnosed patient samples to provide diagnostic predictions. An iterative improvement strategy was employed, where new data are continuously integrated to refine the IMD-specific signatures. The algorithm's performance was evaluated through both the current study and a case study using literature-derived data.
The algorithm demonstrated iterative improvement with each training round, correctly identifying the diagnosis within top 3 potential IMDs in 60% of samples (top 1 in 42%). The case study applied the method to literature-based data comprising 95 IMD samples (11 different IMDs) and 68 controls, yielding a correct diagnosis in 73.5% of cases.
These results demonstrate that the algorithm provides a flexible, data-driven framework for continuous improvement in IMD diagnosis, even with limited number of samples.
© 2025. The Author(s).

Suspended animation states allow organisms to survive extreme environments. The African turquoise killifish has evolved diapause as a form of suspended development to survive a complete drought. However, the mechanisms underlying the evolution of extreme survival states are unknown. To understand diapause evolution, we performed integrative multi-omics (gene expression, chromatin accessibility, and lipidomics) in the embryos of multiple killifish species. We find that diapause evolved by a recent remodeling of regulatory elements at very ancient gene duplicates (paralogs) present in all vertebrates. CRISPR-Cas9-based perturbations identify the transcription factors REST/NRSF and FOXOs as critical for the diapause gene expression program, including genes involved in lipid metabolism. Indeed, diapause shows a distinct lipid profile, with an increase in triglycerides with very-long-chain fatty acids. Our work suggests a mechanism for the evolution of complex adaptations and offers strategies to promote long-term survival by activating suspended animation programs in other species.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Palmitic acid (PA) is the most common fatty acid in humans and mediates palmitoylation through its conversion into palmitoyl coenzyme A. Although palmitoylation affects many proteins, its pathophysiological functions are only partially understood. Here we demonstrate that PA acts as a molecular checkpoint of lipid reprogramming in HepG2 and Hep3B cells. The zinc finger DHHC-type palmitoyltransferase 23 (ZDHHC23) mediates the palmitoylation of plant homeodomain finger protein 2 (PHF2), subsequently enhancing ubiquitin-dependent degradation of PHF2. This study also reveals that PHF2 functions as a tumor suppressor by acting as an E3 ubiquitin ligase of sterol regulatory element-binding protein 1c (SREBP1c), a master transcription factor of lipogenesis. PHF2 directly destabilizes SREBP1c and reduces SREBP1c-dependent lipogenesis. Notably, SREBP1c increases free fatty acids in hepatocellular carcinoma (HCC) cells, and the consequent PA induction triggers the PHF2/SREBP1c axis. Since PA seems central to activating this axis, we suggest that levels of dietary PA should be carefully monitored in patients with HCC.
© 2023. Springer Nature Limited.

Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, provides a potential treatment avenue for drug-resistant cancers and may play a role in the pathology of some degenerative diseases. Identifying the subcellular membranes essential for ferroptosis and the sequence of their peroxidation will illuminate drug discovery strategies and ferroptosis-relevant disease mechanisms. In this study, we employed fluorescence and stimulated Raman scattering imaging to examine the structure-activity-distribution relationship of ferroptosis-modulating compounds. We found that, although lipid peroxidation in various subcellular membranes can induce ferroptosis, the endoplasmic reticulum (ER) membrane is a key site of lipid peroxidation. Our results suggest an ordered progression model of membrane peroxidation during ferroptosis that accumulates initially in the ER membrane and later in the plasma membrane. Thus, the design of ER-targeted inhibitors and inducers of ferroptosis may be used to optimally control the dynamics of lipid peroxidation in cells undergoing ferroptosis.
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.