Biology subjects

Najjar, S. M.

Publications and source records attributed to Najjar, S. M..

4 recordsLinked to original sources

bioRxiv2025

Defective insulin clearance plays a primary role in the pathogenesis of chronic kidney disease in mice with null deletion of Ceacam2 gene

Endogenous insulin clearance occurs primarily in hepatocytes and to a lower extent in kidneys proximal tubule cells (KPTCs). CEACAM1 promotes receptor-mediated insulin uptake to be degraded in hepatocytes in a phosphorylation-dependent manner. Its deletion/inactivation causes hyperinsulinemia-driven insulin resistance, steatohepatitis and liver fibrosis. CEACAM2, the dominant CEACAM protein in murine KPTCs, shares a high homology with CEACAM1. Thus, we examined whether it regulates renal insulin disposal to maintain renal homeostasis. KPTCs derived from Ceacam2 null mice (Cc2-/-) exhibited lower receptor-mediated insulin uptake. Combined with the gradual decline in CEACAM1-dependent hepatic insulin clearance, impaired renal insulin clearance contributed to chronic hyperinsulinemia and insulin resistance starting at 10 months of age in Cc2-/-males. This was followed by proteinuria and reduced glomerular filtration rate in association with glomerulosclerosis and tubulointerstitial damage. Increased collagen deposition in Cc2-/- kidneys could be mediated in part, by hyperinsulinemia-driven activation of the 5{beta}1 integrin-focal adhesion kinase (FAK) signaling pathways. Together, the data demonstrated that loss of CEACAM2 impaired renal insulin clearance that contributed to hyperinsulinemia and resultant insulin resistance, followed by kidney dysfunction and renal fibrosis. This study provided an in vivo demonstration of the regulation of kidney function by insulin clearance along the liver-kidney axis.

physiology↗

bioRxiv2025

Ablation of the evolutionarily acquired functions of the Atp1b4 gene in mice protects against obesity and increases metabolic capacity

The co-option of vertebrate orthologous ATP1B4 genes in placental mammals has radically altered the properties of the encoded BetaM proteins, which are genuine {beta}-subunits of Na,K-ATPases in lower vertebrates. Eutherian BetaM acquired an extended Glu-rich N-terminal domain resulting in complete loss of its ancestral function and became skeletal and cardiac muscle-specific component of the inner nuclear membrane. BetaM is expressed at the highest level during perinatal development and is implicated in gene regulation (Pestov et al., Proc Natl Acad Sci U S A. 2007). Here we report the long-term consequences of the Atp1b4 ablation on metabolic parameters in adult mice. BetaM deficient (Atp1b4-/Y) mice have significantly lower body weight and remarkably low adiposity. They exhibit lower fasting blood glucose, enhanced insulin sensitivity, and improved glucose tolerance as compared to their wild type littermates. Knockout mice display higher heat production, increased food intake, elevated oxygen consumption especially in darkness, and higher locomotor activity. The lower respiratory exchange ratio of knockout mice indicates that fat from the diet is metabolized rather than deposited as storage. These robust changes in mouse metabolic parameters induced by Atp1b4 disruption clearly demonstrate that eutherian BetaM plays an important role in the regulation of adult mouse metabolism. Ablation of Atp1b4, leading to the loss of evolutionarily acquired BetaM functions, serves as a model for a potential alternative pathway in mammalian evolution. Essentially, Atp1b4 ablation simulates a scenario where a specific stage in mammalian evolution is bypassed. Our results suggest that bypassing the co-option of Atp1b4 potentially reduces susceptibility to obesity.

evolutionary biology↗

bioRxiv2024

Conditional deletion of CEACAM1 causes hepatic stellate cell activation

ObjectivesHepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with MASH. Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPAR{gamma} on CEACAM1 transcriptoin and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation. MethodsWe examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generated LratCre+Cc1fl/fl mutants with conditional Ceacam1 deletion in HSCs and characterized their MASH phenotype. Media transfer experiments were employed to examine whether media from mutant human and murine HSCs activate their wild-type counterparts. ResultsLratCre+Cc1fl/fl mutants displayed hepatic inflammation and fibrosis but without insulin resistance or hepatic steatosis. Their HSCs, like KD-LX2 cells, underwent myofibroblastic transformation and their media activated wild-type HDCs. This was inhibited by nicotinic acid treatment which stemmed the release of IL-6 and fatty acids, both of which activate the epidermal growth factor receptor (EGFR) tyrosine kinase. Gefitinib inhibition of EGFR and its downstream NF-{kappa}B/IL-6/STAT3 inflammatory and MAPK-proliferation pathways also blunted HSCs activation in the absence of CEACAM1. ConclusionsLoss of CEACAM1 in HSCs provoked their myofibroblastic transformation in the absence of insulin resistance and hepatic steatosis. This response is mediated by autocrine HSCs activation of the EGFR pathway that amplifies inflammation and proliferation.

physiology↗

bioRxiv2022

Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction

Defects in insulin processing and granule maturation are linked to pancreatic beta-cell failure during type 2 diabetes (T2D). Phosphatidylinositol transfer protein alpha (PITPNA) stimulates activity of phosphatidylinositol (PtdIns) 4-OH kinase to produce sufficient PtdIns-4-phosphate (PtdIns-4-P) in the trans-Golgi network to promote insulin granule maturation. PITPNA in beta-cells of T2D human subjects is markedly reduced suggesting its depletion accompanies beta-cell dysfunction. Conditional deletion of Pitpna in the beta-cells of Ins-Cre;Pitpnaflox/flox mice leads to hyperglycemia resulting from decreased glucose-stimulated insulin secretion (GSIS) and reduced pancreatic beta-cell mass. Furthermore, PITPNA silencing in human islets confirmed its role in PtdIns-4-P synthesis and led to impaired insulin granule maturation and docking, GSIS, and proinsulin processing with evidence of ER stress. Restoration of PITPNA in islets of T2D human subjects reversed these beta-cell defects and identify PITPNA as a critical target linked to beta-cell failure in T2D.

cell biology↗