STK25- a new key regulator of metabolic profile and a possible target for anti-diabetic drug
Year: 2017
Type: dissertation
Abstract: Type 2 diabetes (T2D) affects at least 285 million people worldwide and its\nprevalence is rapidly increasing. Understanding the molecular mechanisms controlling\nectopic lipid deposition and insulin response in metabolic tissues is essential for\ndeveloping new pharmacological strategies to effectively treat T2D. Obesity and\noverweigh are the main risk factors for developing T2D, but nonalcoholic fatty liver\ndisease (NAFLD) also contributes to the pathogenesis of T2D. Today, achieving good\nglycemic control in T2D patients with the current treatment alternatives remains\nchallenging and no specific therapy exists against NAFLD.\nIn this thesis, we describe protein kinase STK25 as a new key regulator of ectopic\nlipid deposition in skeletal muscle, liver and pancreas as well as whole-body\nmetabolism. We have found that STK25 overexpression in mice challenged with a\nhigh-fat diet (HFD) results in an increased ectopic lipid deposition in skeletal muscle\nand pancreas, accompanied by an aggravated fibrosis and inflammation. The\noverexpression of STK25 also leads to impairments in β-oxidation and decrease in in\nvivo insulin-stimulated glucose uptake in skeletal muscle and reduced endurance\nexercise capacity in mice. The pancreas of Stk25 transgenic animals shows a\nsignificant decrease in islet β/α-cell ratio and alterations in the islet architecture with\nan increased presence of α-cells within the islet core, together with an impaired insulin\nproduction during IPGTT after a HFD challenge. We also show that treatment with\nStk25 antisense oligonucleotides in obese mice protects against HFD-induced liver\nsteatosis, glucose intolerance and insulin resistance. In addition, we found a significant\npositive correlation between nonalcoholic steatohepatitis (NASH) development and\nSTK25 protein abundance in human liver biopsies. Furthermore, we have identified\nfour common non-linked SNPs in the human STK25 gene that are associated with\naltered liver fat: two associated with increased hepatic fat levels and two associated\nwith decreased levels.\nTaken together, our studies suggest that pharmacological inhibition of STK25\npotentially provides a new-in-class therapeutic strategy for the treatment of NAFLD,\nT2D and related metabolic complications.
Author: Esther Nuñez‐Durán
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2772393278