Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic triglycerides (TG) and hyperglycemia arising due to persistent insulin resistance, and is profoundly linked to obesity. However, there is currently no established treatment for NAFLD in obese human subjects. We previously isolated Helz2, the expression of which was upregulated in human and mouse NAFLD, and its deletion activated the hepatic expression of functional leptin receptor long form (Leprb) and suppressed NAFLD development and body weight (BW) gain in obese mice. A high-throughput assay of small-molecule drugs revealed that guanabenz acetate (Ga), originally used to treat hypertension, possesses a high affinity constant against HELZ2, and its administration activates LEPRB expression in HepG2 cells in vitro. The chronic oral administration of Ga shows the selective leptin sensitization in the liver via upregulation of hepatic Leprb expression, which affects expression of genes involved in lipogenesis and fatty acid β-oxidation and diminishes hepatocyte hypertrophy with droplets enriched in TG in high-fat diet-induced obese mice. This activity significantly improves insulin resistance to decrease hyperglycemia and hepatocyte and adipocyte weights, resulting in BW reduction without reducing food intake. Regarding drug repositioning, Ga has the potential to effectively treat NAFLD and hyperglycemia in obese patients.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic triglycerides (TG) and hyperglycemia arising due to persistent insulin resistance, and is profoundly linked to obesity
The present findings clearly demonstrate that the chronic oral administration of small-molecule guanabenz acetate (Ga), which possesses a high-affinity constant against HELZ2 and activates hepatic Leprb expression in vitro and in vivo, prevents the excessive accumulation of TG in hepatocytes and attenuates hyperglycemia associated with insulin resistance in obese mice fed HFD
A previous study showed that an intraperitoneal injection of Ga every other day for 1 week at a dose of 4 mg/kg body weight (BW) decreased blood insulin levels with increased blood glucose levels, possibly due to its toxic induction of anorexia in HFD-induced obese m ice[35]
Summary
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic triglycerides (TG) and hyperglycemia arising due to persistent insulin resistance, and is profoundly linked to obesity. The chronic oral administration of Ga shows the selective leptin sensitization in the liver via upregulation of hepatic Leprb expression, which affects expression of genes involved in lipogenesis and fatty acid β-oxidation and diminishes hepatocyte hypertrophy with droplets enriched in TG in high-fat diet-induced obese mice This activity significantly improves insulin resistance to decrease hyperglycemia and hepatocyte and adipocyte weights, resulting in BW reduction without reducing food intake. We showed that Helz[2] suppressed the activity of the leptin receptor p romoter[22] in conjunction with nuclear transcription factors (in preparation) These findings collectively imply that inhibition of Helz[2] function clearly upregulates the Leprb expression in the liver and that hepatic Helz[2] is a potential target molecule for the treatment of fatty liver and hyperglycemia
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