Evidence map›Paper›PMID 42772455›Full record

ArticleMolecular metabolism2026

Adult-onset deficiency of β-klotho in the liver reveals a novel role in lipid homeostasis.

Alexandra S Aaldijk, Cristy R C Verzijl, Milaine V Hovingh, Nicolette C A Huijkman, Marieke Smit, Niels J Kloosterhuis, Niels L Mulder, Rick Havinga, Albert Gerding, Trijnie Bos and 6 more

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Article in Molecular metabolism, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

16 authors.

Alexandra S AaldijkDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Cristy R C VerzijlDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Milaine V HovinghDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Nicolette C A HuijkmanDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Marieke SmitDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Niels J KloosterhuisDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Niels L MulderDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Rick HavingaDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Albert GerdingDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Trijnie BosDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Mirjam KosterDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Mariska de GraafDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands; Interfaculty Mass Spectrometry Center, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.
Justina C WoltersDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands; Interfaculty Mass Spectrometry Center, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.
Bart van de SluisDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands; Transgenic Mouse Clinic for Aging Research, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.
Dicky StruikDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Johan W JonkerDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands. Electronic address: j.w.jonker@umcg.nl.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundβ-klotho (KLB), the obligate co-receptor for fibroblast growth factor (FGF) 19 and 21 signalling, has emerged as a therapeutic target for metabolic disease. Current understanding of KLB function is based largely on germline knockout mouse models, where developmental abnormalities obscure its function in adult physiology. Here, we used somatic hepatocyte-specific gene editing in adult mice to define hepatic KLB function.

methodsHepatocyte-specific KLB deficiency was induced by retro-orbital delivery of adeno-associated virus particles containing guide RNAs targeting Klb in adult male mice expressing Cas9 in the liver. Following transduction, mice were maintained on a 4-week chow diet or a 12-week high-fat diet, prior to comprehensive metabolic and biochemical phenotyping.

resultsAdult-onset hepatic KLB deficiency did not alter body weight or composition, indicating that reduced bodyweight in germline models reflects developmental effects. In line with previous studies, KLB deficiency resulted in derepressed bile acid synthesis, elevated faecal bile acid excretion, and a shift towards a more hydrophobic bile acid pool. Importantly, we also uncovered a role for hepatic KLB in regulating lipid homeostasis. Chow-fed KLB-deficient mice exhibited reduced circulating very-low-density lipoprotein levels (VLDL) with marked hepatic triglyceride accumulation, suggesting altered VLDL metabolism as a potential mechanism driving steatosis.

conclusionsUsing an adult-onset liver-specific knockout model, we disentangled KLB function from developmental confounders and established KLB as a critical regulator of adult lipid and lipoprotein homeostasis. Our study redefines the physiological role of KLB in hepatic metabolism and has important implications for the interpretation of FGF19/KLB-directed therapies for metabolic diseases.

Indexed as

Lipid MetabolismLiverMembrane ProteinsAnimalsBile Acids and SaltsDiet, High-FatFibroblast Growth FactorsHepatocytesHomeostasisKlotho ProteinsLipoproteins, VLDLMaleMiceMice, Inbred C57BLMice, KnockoutBile Acids and SaltsFibroblast Growth FactorsKlb protein, mouseKlotho ProteinsLipoproteins, VLDLMembrane ProteinsBile acidsFGF19FGF21LipoproteinLiver metabolismMASLDSomaticVLDL

Identifiers

PMID42772455
PMCPMC13658126

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