Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver Disease
Artikel i vetenskaplig tidskrift, 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

Författare

Emmelie Cansby

Sahlgrenska universitetssjukhuset

Esther Nuñez-Durán

Sahlgrenska universitetssjukhuset

Elin Magnusson

Sahlgrenska universitetssjukhuset

Manoj Amrutkar

Universitetet i Oslo

Sheri L. Booten

Ionis Pharmaceuticals

Nagaraj M. Kulkarni

Sahlgrenska universitetssjukhuset

L. Thomas Svensson

Science for Life Laboratory (SciLifeLab)

Chalmers, Biologi och bioteknik

Jan Borén

Wallenberg Lab.

H. U. Marschall

Wallenberg Lab.

Mariam Aghajan

Ionis Pharmaceuticals

Margit Mahlapuu

Sahlgrenska universitetssjukhuset

CMGH Cellular and Molecular Gastroenterology and Hepatology

2352-345X (eISSN)

Vol. 7 3 597-618

Ämneskategorier

Immunologi inom det medicinska området

Farmakologi och toxikologi

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

DOI

10.1016/j.jcmgh.2018.12.004

Mer information

Senast uppdaterat

2019-07-22