Angptl4 integrates dietary and microbial signals to disrupt gut barrier function in MASH

Damien Chua  ¹ , Zun Siong Low  ² , Joseph Han Sol Kim  ² , Yin Hao Lee  ^{3   4} , Rattanaporn Kiatbumrung  ⁵ , Pornjira Somnark  ⁵ , Min Xu  ⁶ , Yue Shi  ⁶ , Gourav Kaushal  ⁷ , Marcus Ivan Gerard Vos  ² , Aparna Mahadevan  ² , Natalie Hooi  ² , Mathan Raj  ⁸ , Ekaterina Sviriaeva  ² , Beiming Cui  ⁹ , Shaun Tan  ² , Kazuyuki Kasahara  ² , Chun Loong Ho  ⁹ , Walter Wahli  ^{2   10   11} , Kuo Chao Yew  ¹² , Sunny H Wong  ^{2   12} , Christine Cheung  ^{2   13} , Mintu Pal  ¹⁴ , Ru Zhang  ^{15   16   17} , Natthaya Chuaypen  ⁵ , Pisit Tangkijvanich  ⁵ , Hong Sheng Cheng  ¹⁸ , Liang Li  ¹⁹ , Nguan Soon Tan  ^{20   21}

Affiliations

• PMID: 42173835
• DOI: 10.1038/s41467-026-72575-6

Free article

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to liver morbidity, yet mechanisms linking gut barrier dysfunction to early progression remains poorly defined. We identify intestinal angiopoietin-like 4 (Angptl4) as a central integrator of dietary and microbial signals that governs barrier integrity and hepatic oxidative stress, key early MASLD features. Using intestinal-specific Angptl4 knockout mice, mechanistic in vitro systems, humanized microbiota models, and multi-cohort human studies, we show that intestinal Angptl4 expression is regulated by dietary fatty acids via PPARα signaling and microbiota-derived pattern-recognition pathways, including flagellin-activated-TLR5-EGR1 activation, alongside diet-associated shifts in TLR signaling. These signals destabilize epithelial barriers, amplifying gut-to-liver metabolic and microbial flux. In human cohorts, fecal Angptl4 increases with dysbiosis and metabolic dysfunction, capturing a gut barrier-related dimension distinct from endotoxemia or acute injury. Thus, intestinal Angptl4 emerges as a mechanistic hub linking diet, microbiota, and gut-liver dysfunction, supporting precision barrier-targeted strategies in MASLD.

Intersecting experimental evolution and CRISPR screens to identify novel toxin resistance loci

Michele Marconcini, Steeve Cruchet, Srishti Goswami, Raghuvir Viswanatha, Matthew Butnaru, Joydeep De, Camilla Roselli, Dafni Hadjieconomou, Norbert Perrimon, Stephanie E Mohr, Richard Benton

• PMID: 42079102
• PMCID: PMC13131652
• DOI: 10.1101/2025.07.23.666417

Abstract

Understanding toxin resistance in insects is key to appreciate niche adaptations but remains challenging due to its often-polygenic basis. A well-known example is the specialized association of Drosophila sechellia with noni fruit ( Morinda citrifolia ), which is toxic to most other insects, including the closely-related drosophilids D. simulans and D. melanogaster . Noni toxicity is due to its high concentration of octanoic acid (OA), but the mechanisms that determine sensitivity or resistance to OA remain poorly understood. Here, we experimentally-evolved D. simulans with increased OA resistance, identifying multiple loci under selection. Cross-referencing these with a genome-wide, OA-resistance CRISPR screen in a D. melanogaster cell line highlighted two proteins: Kraken, a putative detoxification enzyme expressed in digestive and renal tissues, and Alkbh7, a mitochondrial protein linked to fatty acid metabolism. Both genes show elevated expression in D. sechellia and OA-resistant D. simulans . In D. melanogaster , kraken mutants are more OA-sensitive, while Alkbh7 overexpression increased OA resistance. Importantly, mutation of these genes in D. sechellia reduced OA tolerance. Our identification of genes underlying OA resistance in laboratory and natural contexts demonstrates how complementary, cross-species selection approaches can provide insights into complex mechanisms of toxin susceptibility and adaptation, and have practical applications in the characterization of novel insecticides.

Global genetic interaction network of a human cell maps conserved principles and informs functional interpretation of gene co-essentiality profiles

Maximilian Billmann  ¹ , Michael Costanzo  ² , Xiang Zhang  ³ , Arshia Z Hassan  ³ , Mahfuzur Rahman  ³ , Kevin R Brown  ⁴ , Katherine S Chan  ⁴ , Amy Hin Yan Tong  ² , Carles Pons  ⁵ , Henry N Ward  ⁶ , Catherine Ross  ² , Jolanda van Leeuwen  ² , Michael Aregger  ² , Keith A Lawson  ⁷ , Barbara Mair  ² , Amy F Roth  ⁸ , Nesli E Sen  ⁹ , Duncan T Forster  ⁷ , Guihong Tan  ² , Patricia Mero  ⁴ , Sanna N Masud  ¹⁰ , Yoonkyu Lee  ⁶ , Magali Aguilera-Uribe  ¹¹ , Matej Ušaj  ² , Sylvia M T Almeida  ⁷ , Kamaldeep Aulakh  ⁴ , Urvi Bhojoo  ⁷ , Saba Birkadze  ¹¹ , Nathaniel Budijono  ³ , Xunhui Cai  ¹² , Joseph J Caumanns  ² , Jordan J Chalmers  ¹¹ , Megha Chandrashekhar  ⁷ , Daniel Chang  ³ , Ryan Climie  ² , Kuheli Dasgupta  ¹¹ , Adrian Drazic  ¹³ , Jose I Rojas Echenique  ² , Rafael Gacesa  ² , Adrian Granda Farias  ¹¹ , Andrea Habsid  ⁴ , Ira Horecka  ⁷ , Kristin Kantautas  ⁷ , Fenghu Ji  ¹² , Dae-Kyum Kim  ¹⁴ , Seon Yong Lee  ⁴ , Wendy Liang  ² , Hyobin Julianne Lim  ⁷ , Kevin Lin  ⁶ , Xueyibing Lu  ³ , Michael Maier  ¹⁵ , Babak Nami  ⁴ , Allison Nixon  ⁷ , Nicholas Mikolajewicz  ⁴ , Milad Mokhtaridoost  ⁴ , Lyudmila Nedyalkova  ² , Thomas Rohde  ¹⁶ , Maria Sartori Rodrigues  ² , Martin Soste  ² , Eric Schultz  ³ , Wen Wang  ³ , Ashwin Seetharaman  ² , Ermira Shuteriqi  ² , Olga Sizova  ⁴ , David Thomson Taylor  ¹⁷ , Maria Tereshchenko  ¹⁸ , David Tieu  ⁷ , Jacob Turowec  ² , Tajinder Ubhi  ¹⁹ , Sylvia Varland  ¹³ , Kyle E Wang  ⁷ , Zi Yang Wang  ⁷ , Jiarun Wei  ¹¹ , Yu-Xi Xiao  ¹¹ , Philipp G Maass  ¹¹ , Bruno Reversade  ¹⁵ , Grant W Brown  ¹⁹ , Benjamin F Cravatt  ²⁰ , Scott J Dixon  ²¹ , Haley D M Wyatt  ¹⁸ , Hannes L Röst  ² , Frederick P Roth  ²² , Tian Xia  ²³ , Gary D Bader  ⁷ , Robbie Loewith  ⁹ , Nicholas G Davis  ⁸ , Brenda Andrews  ²⁴ , Chad L Myers  ²⁵ , Jason Moffat  ²⁶ , Charles Boone  ²⁷

Affiliations

• PMID: 42049019
• DOI: 10.1016/j.cell.2026.03.044

Abstract

Deciphering how genes interact within human cells is essential for understanding their functional wiring and for developing targeted therapeutic strategies. In this study, we present a genome-scale map of genetic interactions in the human haploid cell line HAP1, based on CRISPR-based perturbation of ∼4 million gene pairs. The resulting network comprises ∼89,000 high-confidence gene-gene interactions, organizing genes into hierarchical modules corresponding to protein complexes and pathways, biological processes, and cellular compartments, mirroring principles observed in yeast and highlighting the functional architecture of a human cell. This large-scale genetic network complements the DepMap gene co-essentiality network by capturing unique functional information, uncovering roles of previously uncharacterized genes, and identifying molecular determinants of cancer-cell-line-specific genetic dependencies. This study presents a general data-driven strategy for systematically exploring the roles of genes and their functional connections in human cell lines.

Keywords: genetic interactions; genetic network conservation; genetic suppression; genome-scale genetic interaction network; genome-wide CRISPR screens; human haploid cells; synthetic lethality.

Hepatic FGF21 is not required for fasting metabolism but guides protein appetite post energy depletion

Justine Bruse  ¹ , Clothilde Marbach  ^{1   2} , Arnaud Polizzi  ¹ , Tatiana Landre  ³ , Juliette Salvi  ³ , Valérie Alquier-Bacquie  ¹ , Shiou-Ping Chen  ⁴ , Marine Huillet  ¹ , Clémence Rives  ¹ , Céline M P Martin  ¹ , Prunelle Perrier  ¹ , Fadila Benhamed  ⁵ , Marion Régnier  ⁵ , Stefan Weger  ⁶ , Claire Naylies  ¹ , Yannick Lippi  ¹ , Caroline Sommer  ¹ , Mikael Albin  ¹ , Frédéric Lasserre  ¹ , Thierry Levade  ^{7   8} , Michael Schupp  ⁹ , Laurence Gamet-Payrastre  ¹ , Léon Kautz  ¹⁰ , Nicolas Loiseau  ¹ , Walter Wahli  ^{1   11} , Sandrine Ellero-Simatos  ¹ , Céline Cruciani-Guglielmacci  ⁴ , Alexandra Montagner  ¹² , Alexandre Benani  ³ , Catherine Postic  ⁵ , Hervé Guillou ^{#  13} , Anne Fougerat ^{#  14}

Affiliations

• PMID: 42045447
• DOI: 10.1038/s44319-026-00790-9

Free article

Abstract

Fasting initiates a coordinated metabolic response to preserve energy balance. As glycogen stores are depleted, the body transitions to mobilizing fatty acids from adipose tissue and generating ketone bodies in the liver to sustain the function of vital organs. A network of hormonal signals and transcriptional programs coordinate these adaptations. Among these, the hepatokine fibroblast growth factor 21 (FGF21) is strongly upregulated during fasting and has been proposed as a key mediator of the fasting response. To investigate the physiological functions of FGF21, we study mice with hepatocyte-specific deletion of Fgf21. Although the liver is the primary source of circulating FGF21 during fasting, its absence in hepatocytes does not alter typical fasting-induced gene expression or key metabolic pathways such as hepatic gluconeogenesis, adipose tissue lipolysis, or ketone production. Instead, we uncover a distinct role for FGF21 in promoting protein appetite following a fast. These findings challenge the conventional view of hepatocyte-produced FGF21 as a fasting-acting hormone and reveal a more specialized function in guiding nutrient selection after energy depletion.