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Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and correlates positively with PPARγ-induced lipogenic signaling. High-fat-fed PTPRK knockout male and female mice have lower weight gain and reduced hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6-bisphosphatase 1 and glycolysis as PTPRK targets in metabolic reprogramming. Mechanistically, PTPRK-induced glycolysis enhances PPARγ and lipogenesis in hepatocytes. Silencing PTPRK in liver cancer cell lines reduces colony-forming capacity and high-fat-fed PTPRK knockout mice exposed to a hepatic carcinogen develop smaller tumours. Our study defines the role of PTPRK in the regulation of hepatic glycolysis, lipid metabolism, and tumour development in obesity. PTPRK is a key protein in the transformation of normal to tumorigenic liver cells in obesity, providing fuel and lipids. Here, the authors show that genetic deletion of PTPRK in mice protects against fatty liver in an obesogenic diet and the development of liver cancer. [ABSTRACT FROM AUTHOR]

Background and Objectives: Renal elimination of amikacin and other aminoglycosides is slowed down in sepsis-induced acute kidney injury increasing the risk of adverse effects. Since neutrophil gelatinase-associated lipocalin (NGAL) and aminoglycosides share the mechanisms for renal excretion, the predictive power of NGAL was examined towards the changes in amikacin pharmacokinetics during early endotoxemia in anesthetized Wistar rats. Methods: Endogenous biomarkers of inflammation and acute kidney injury were assessed including NGAL in saline-injected controls and two groups of rats challenged with an intravenous injection of bacterial lipopolysaccharide (5 mg/kg)—a fluid-resuscitated group (LPS) and a fluid-resuscitated group infused intravenously with 8 μg/kg/h terlipressin (LPS-T). Sinistrin and amikacin were infused to measure glomerular filtration rate (GFR) and amikacin clearance (CLam). The investigations included blood gas analysis, chemistry and hematology tests and assessment of urine output, creatinine clearance (CLcr) and sinistrin clearance (CLsini). Results: Within 3 h of injection, systemic and renal inflammatory responses were induced by lipopolysaccharide. Gene and protein expression of NGAL was increased in the kidneys and the concentrations of NGAL in the plasma (pNGAL) and urine rose 4- to 38-fold (P < 0.01). The decreases in CLam and the GFR markers (CLcr, CLsini) were proportional, reflecting the extent to which endotoxemia impaired the major elimination mechanism for the drug. Terlipressin attenuated lipopolysaccharide-induced renal dysfunction (urine output, CLcr, CLsini) and accelerated CLam. The pNGAL showed a strong association with the CLsini (rs = − 0.77, P < 0.0005). Concerning prediction of CLam, pNGAL was comparable to CLcr (mean error − 24%) and inferior to CLsini (mean error − 6.4%), while the measurement of NGAL in urine gave unsatisfactory results. Conclusions: During early endotoxemia in the rat, pNGAL has a moderate predictive ability towards CLam. Clinical studies should verify whether pNGAL can support individualized dosing of aminoglycosides to septic patients. [ABSTRACT FROM AUTHOR]