Biology subjects

Lacombe, J.

Publications and source records attributed to Lacombe, J..

5 recordsLinked to original sources

bioRxiv2026

The vitamin K oxidoreductase VKORC1L1 prevents oxidative stress in hepatocytes and protects from MASLD and hepatocellular carcinoma

Generation of vitamin K hydroxyquinone (VKH2) by vitamin K oxidoreductase 1 (VKORC1) is essential for the {gamma}-carboxylation of clotting factors by hepatocytes. Here, we uncover a non-redundant function of the vitamin K oxidoreductase paralogue VKORC1L1 in liver homeostasis. Mice lacking Vkorc1l1 globally or specifically in hepatocytes exhibit normal coagulation yet develop progressive metabolic dysfunction-associated steatotic liver disease (MASLD). Transcriptomic profiling revealed early dysregulation of lipid metabolism and inflammatory pathways, converging on human MASLD signatures, while genetic colocalization analyses implicate human VKORC1L1 variants in MASLD and liver fat accumulation. Mechanistically, VKORC1L1 prevents reactive oxygen species overload and DNA damage through vitamin K reduction, independently of {gamma}-carboxylation. Loss of VKORC1L1 induces oxidative stress, chromosome instability, and aneuploidy, culminating in steatohepatitic hepatocellular carcinoma (HCC). Conversely, pharmacological vitamin K supplementation rescues oxidative stress, MASLD and DNA damage in Vkorc1l1-deficient mice. These findings redefine vitamin K as a hepatic antioxidant and identify VKORC1L1 as a safeguard against MASLD and HCC.

cancer biology↗

bioRxiv2025

Vitamin K-dependent carboxylation in osteoblasts regulates bone resorption through GAS6

Studies in humans suggest that vitamin K is involved in the regulation of bone remodeling, but the precise mechanism at play remains unknown. In cells, vitamin K functions as a co-factor for the {gamma}-glutamyl carboxylase (GGCX), an enzyme responsible for the conversion of glutamic acid residues (Glu) into {gamma}-carboxyglutamic acid (Gla) residues in secreted proteins. We aim here at determining the role of {gamma}-carboxylation in bone remodeling and at identifying the Gla protein(s) involved. We show that male mice lacking {gamma}-carboxylation specifically in osteoblasts (Ggcxflox/flox;OCN-Cre) have increased bone mass at 6 months of age due to a reduced number of multinucleated bone resorbing osteoclasts. In co-culture experiments, Ggcx-deficient osteoblasts were less effective than control osteoblasts at supporting osteoclast formation. Among known Gla proteins, we identify GAS6 as an osteoblast-secreted {gamma}-carboxylated factor which signals to differentiating osteoclasts. The GAS6 receptors MerTK and AXL are expressed in pre-osteoclasts and pharmacological inhibitors of AXL and MerTK block osteoclast generation in co-culture. Conversely, recombinant {gamma}-carboxylated GAS6 dose-dependently increases the size of osteoclasts and the number of nuclei per osteoclast in culture. GAS6 marginally affected the induction of osteoclast-specific genes during osteoclast differentiation but significantly increased pre-osteoclast fusion. Finally, increasing bone marrow GAS6 level in transgenic male mice was sufficient to increase the number and size of osteoclasts and to decrease bone mass. This work identifies GAS6 as a novel osteoblast-derived vitamin K-dependent protein regulating osteoclast maturation.

cell biology↗

bioRxiv2023

GAS6 and AXL promote insulin resistance by rewiring insulin signaling and increasing insulin receptor trafficking to late endosomes

Growth-arrest specific 6 (GAS6) is a secreted protein that acts as a ligand for TAM receptors (TYRO3, AXL and MERTK). In humans, GAS6 circulating levels and genetic variations in GAS6 are associated with hyperglycemia and increased risk of type 2 diabetes. However, the mechanisms by which GAS6 influences glucose metabolism are not understood. Here, we show that Gas6 deficiency in mice increases insulin sensitivity and protects from diet-induced insulin resistance. Conversely, increasing GAS6 circulating levels is sufficient to reduce insulin sensitivity in vivo. GAS6 inhibits the activation of the insulin receptor (IR) and reduces insulin response in muscle cells in vitro and in vivo. Mechanistically, AXL and IR fom a complex, while GAS6 reprograms signaling pathways downstream of IR. This results in increased IR endocytosis following insulin treatment. This study contributes to a better understanding of the cellular and molecular mechanisms by which GAS6 and AXL influence insulin sensitivity. ARTICLE HIGHLIGHTSO_LIGAS6 deficient mice are characterized by improved glucose tolerance, increased insulin sensitivity and are protected from diet-induced insulin resistance. C_LIO_LIThe GAS6 receptor AXL is expressed in muscle cells and forms a complex with the insulin receptor. C_LIO_LIGAS6 reprograms insulin signaling by modulating the phosphorylation of proteins implicated in endocytosis, vesicle-mediated transport, and membrane trafficking. C_LIO_LIAXL and GAS6 promotes insulin receptor endocytosis following insulin treatment. C_LI

physiology↗

bioRxiv2022

Vitamin K-dependent carboxylation of junctate regulates calcium flux and adaptation to metabolic stress in β-cells

Vitamin K is a micronutrient necessary for the {gamma}-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Clinical studies have recently implicated vitamin K in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show that mouse {beta}-cells lacking {gamma}-carboxylation fail to adapt their insulin secretion in the context of age-related insulin resistance or diet-induced {beta}-cell stress. In human islets, {gamma}-carboxylase expression positively correlates with improved insulin secretion in response to glucose. We identified Endoplasmic Reticulum Gla Protein (ERGP) as a novel {gamma}-carboxylated ER-resident calcium-binding protein expressed in {beta}-cells. Mechanistically, {gamma}-carboxylation of ERGP protects cells against calcium overfilling by diminishing STIM1 and Orai1 interaction and restraining store-operated calcium entry. These results reveal a critical role for vitamin K-dependent {gamma}-carboxylation in the regulation of calcium flux in {beta}-cells and in their capacity to adapt to metabolic stress.

cell biology↗

bioRxiv2020

The half-life of the bone-derived hormone osteocalcin is regulated through O-glycosylation in mice, but not in humans

Osteocalcin (OCN) is an osteoblast-derived hormone with pleiotropic physiological functions. Like many peptide hormones, OCN is subjected to post-translational modifications (PTMs) which control its activity. Here, we uncover O-glycosylation as a novel PTM present on mouse OCN and occurring on a single serine (S8) independently of its carboxylation and endoproteolysis, two other PTMs regulating this hormone. We also show that O-glycosylation increases OCN half-life in plasma ex vivo and in the circulation in vivo. Remarkably, in human OCN (hOCN), the residue corresponding to S8 is a tyrosine (Y12), which is not O-glycosylated. Yet, the Y12S mutation is sufficient to O-glycosylate hOCN and to increase its half-life in plasma compared to wildtype hOCN. These findings reveal an important species difference in OCN regulation, which may explain why serum concentrations of OCN are higher in mouse than in human. The authors have nothing to disclose

biochemistry↗