Administration of small-molecule guanabenz acetate attenuates fatty liver and hyperglycemia associated with obesity

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 highthroughput 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. NAFLD commonly develops with obesity and is the hepatic component of metabolic syndrome, and its prevalence is increasing worldwide 1. NAFLD encompasses a wide spectrum of chronic pathological liver conditions ranging from simple hepatosteatosis to NASH and cirrhosis, and occurs in approximately 25% of adults globally 2. The prevalence of NAFLD is more than 50% among patients with T2DM 3 , and these patients are at an increased risk of liver-related mortality and cardiovascular disease 2, 3. The liver consists of various cell types with hepatocytes being the main parenchymal cells, in which lipid droplets, mainly TG, accumulate, and an excessive TG content in hepatocytes is a hallmark of NAFLD 4,5. An increased liver TG content is a predictor of hepatic insulin resistance, which causes hyperglycemia, independently of visceral adipocyte volumes or body mass index in individuals with obesity 4,5. Insulin resistance is associated with lipid deposition in the peripheral metabolic organs such as the liver, WAT, BAT and skeletal muscle. Moreover, hepatic steatosis in almost all cases has been shown to precede the development of insulin resistance in other peripheral metabolic organs 4-6. Decreasing excessive lipid levels in the liver was reported to attenuate insulin resistance, thereby ameliorating hyperglycemia in subjects with T2DM and/or NAFLD 7-9. A prolonged high blood level of insulin, attributed to hepatic insulin resistance, contributes in the progression of NAFLD to liver fibrosis, NASH and possibly hepatocellular carcinoma 1,10,11. Effective pharmacological treatments are urgently needed to treat N...

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