Journal
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Volume 7, Issue 3, Pages 597-618Publisher
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2018.12.004
Keywords
NAFLD; NASH; Hepatic Steatosis; Liver Fibrosis; Antisense Oligonucleotide Therapy
Categories
Funding
- Swedish Research Council
- European Foundation for the Study of Diabetes/Lilly European Diabetes Research Programme
- West Sweden Avtal om Lakarutbildning och Forskning (ALF) Program
- Novo Nordisk Foundation
- Swedish Heart-Lung Foundation
- Torsten Soderbergs Foundation
- Diabetes Wellness Network Sweden
- Swedish Diabetes Foundation
- Royal Society of Arts and Sciences in Gothenburg
- Wiberg Foundation
- Adlerbert Research Foundation
- I. Hultman Foundation
- S. and E. Goljes Foundation
- F. Neubergh Foundation
- N. Svarts foundation
- L. and J. Gronbergs Foundation
- I.-B. and A. Lundbergs Research Foundation
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BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide. Currently, no specific pharmacologic therapy is available for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the 21st century. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase (STK) 25 as a critical regulator of hepatic lipid partitioning and NAFLD/NASH. Here, we studied the metabolic benefit of liver-specific STK25 inhibitors on NAFLD development and progression in a mouse model of diet-induced obesity. METHODS: We developed a hepatocyte-specific triantennary N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide (ASO) targeting Stk25 and evaluated its effect on NAFLD features in mice after chronic exposure to dietary lipids. RESULTS: We found that systemic administration of hepatocyte-targeting GalNAc-Stk25 ASO in obese mice effectively ameliorated steatosis, inflammatory infiltration, hepatic stellate cell activation, nutritional fibrosis, and hepatocellular damage in the liver compared with mice treated with GalNAc-conjugated nontargeting ASO, without any systemic toxicity or local tolerability concerns. We also observed protection against high-fat-diet-induced hepatic oxidative stress and improved mitochondrial function with Stk25 ASO treatment in mice. Moreover, GalNAc-Stk25 ASO suppressed lipogenic gene expression and acetyl-CoA carboxylase protein abundance in the liver, providing insight into the molecular mechanisms underlying repression of hepatic steatosis. CONCLUSIONS: This study provides in vivo nonclinical proof-of-principle for the metabolic benefit of liver-specific inhibition of STK25 in the context of obesity and warrants future investigations to address the therapeutic potential of GalNAc-Stk25 ASO in the prevention and treatment of NAFLD.
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