Inhibition of Transcriptional Regulator Taz (Wwtr1) by Antisense Oligonucleotide (ASO) Treatment Improves Obesity and Hepatic Steatosis in a Mouse Model of NASH

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a common disorder that affects millions of people around the world. People with fatty liver disease alone are usually asymptomatic until a second insult to the liver, such as oxidative stress, triggers more severe steatosis, inflammation and fibrosis resulting in nonalcoholic steatohepatitis (NASH). The additional stress and damage to the hepatocytes results in the release of signals, such as hedgehog (Hh), to induce the wound-healing response. Data from animal models and human NASH have demonstrated Hh pathway activation correlates with the severity of liver disease. (1). In addition, the transcriptional coactivator, Taz/Wwtr1, was shown to be increased in hepatocytes from human and mouse NASH livers. (2). Based on these findings we performed DGE and qRT-PCR analysis on mice fed a high fat, fructose, and cholesterol (AMLN) diet for 24 weeks and found elevated mRNA expression of Taz in the livers compared to the lean mice. We treated C57B/6 mice fed the AMLN diet for 24 weeks with ASOs targeting Taz RNA. After 12 weeks of Taz ASO treatment, we observed a 95% knockdown in Taz mRNA expression in the liver compared to the control ASO group. This was accompanied by a 38% loss in whole-body fat mass (EchoMRI) and a 69% decrease in epidydimal white adipose tissue weight. Plasma analysis demonstrated a significant decrease in glucose and cholesterol compared to the control ASO levels. In addition, we observed reductions in liver triglyceride content resulting in levels similar to a lean mouse. No improvements in liver fibrosis were observed with Taz ASO treatment. These positive effects on obesity, plasma cholesterol, and liver steatosis suggest that Taz is a potential therapeutic target for preventing the progression of NASH into a more dangerous and irreversible liver disease. Disclosure R. Peralta: None. A.K. Low: Employee; Self; Ionis Pharmaceuticals, Inc.. Other Relationship; Spouse/Partner; Abbott. J. Schmidt: Employee; Self; Ionis Pharmaceuticals, Inc.. Employee; Spouse/Partner; Ionis Pharmaceuticals, Inc.. A. Ferng: None. S. Murray: Employee; Self; Ionis Pharmaceuticals, Inc. S. Guo: Employee; Self; Ionis Pharmaceuticals, Inc..