Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver Disease
Journal article, 2019

Background and 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.

NASH

Hepatic Steatosis

Antisense Oligonucleotide Therapy

Liver Fibrosis

NAFLD

Author

Emmelie Cansby

Sahlgrenska University Hospital

Esther Nuñez-Durán

Sahlgrenska University Hospital

Elin Magnusson

Sahlgrenska University Hospital

Manoj Amrutkar

University of Oslo

Sheri L. Booten

Ionis Pharmaceuticals

Nagaraj M. Kulkarni

Sahlgrenska University Hospital

L. Thomas Svensson

Science for Life Laboratory (SciLifeLab)

Chalmers, Biology and Biological Engineering

Jan Borén

Wallenberg Lab.

H. U. Marschall

Wallenberg Lab.

Mariam Aghajan

Ionis Pharmaceuticals

Margit Mahlapuu

Sahlgrenska University Hospital

CMGH Cellular and Molecular Gastroenterology and Hepatology

2352-345X (eISSN)

Vol. 7 3 597-618

Subject Categories

Immunology in the medical area

Pharmacology and Toxicology

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

DOI

10.1016/j.jcmgh.2018.12.004

More information

Latest update

7/22/2019