Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver Disease

Cell Mol Gastroenterol Hepatol. 2019;7(3):597-618. doi: 10.1016/j.jcmgh.2018.12.004. Epub 2018 Dec 19.

Abstract

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.

Keywords: Antisense Oligonucleotide Therapy; Hepatic Steatosis; Liver Fibrosis; NAFLD; NASH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl-CoA Carboxylase / metabolism
  • Acetylglucosamine / metabolism
  • Animals
  • Apoptosis / drug effects
  • Body Weight / drug effects
  • Diet, High-Fat
  • Gene Expression Regulation / drug effects
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipogenesis / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Obese
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Non-alcoholic Fatty Liver Disease / blood
  • Non-alcoholic Fatty Liver Disease / therapy*
  • Oligonucleotides, Antisense / pharmacology*
  • Organ Size / drug effects
  • Oxidative Stress / drug effects
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • Stk25 protein, mouse
  • Protein Serine-Threonine Kinases
  • Acetyl-CoA Carboxylase
  • Acetylglucosamine