Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder closely linked with type II diabetes (T2D). The progression of NAFLD is associated with the induction of lipogenesis through hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. An increase in lipogenesis induces endoplasmic reticulum (ER) stress and accelerates oxidative liver injury in the pathogenesis of NAFLD. Lobeglitazone, one of thiazolidinediones (TZDs), is used as an antidiabetic drug to lower serum glucose level through an increase in insulin sensitivity. It is known to improve pathological symptoms in animals and humans with NAFLD. However, the underlying molecular mechanism of the protective effects of lobeglitazone against NAFLD has not been elucidated. Here, we show that under the physiological condition of acute lipogenesis, lobeglitazone inhibits hepatic lipid synthesis, the subsequent ER stress, and ω-oxidation of fatty acids by inhibiting the mTORC1 pathway. As a result, lobeglitazone protected mice from lipogenesis-induced oxidative liver injury. Taken together, lobeglitazone might be a suitable drug for the treatment of patients with diabetes and NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD), encompassing a spectrum from simple steatosis to non-alcoholic steatohepatitis (NASH), is associated with metabolic disorders such as obesity, type II diabetes (T2D), and insulin resistance [1,2,3]
To further verify whether lobeglitazone attenuated the accumulation of reactive oxygen species (ROS) under physiological lipogenesis conditions, we examined the amount of nuclear Nrf2 by using nuclear fractionation (Supplementary Figures 1A,B)
To investigate whether lobeglitazone inhibited endoplasmic reticulum (ER) stress, we evaluated the expression of ER stress-related genes, including ER degradation-enhancing α-mannosidase-like protein (EMDM), 78 kDa glucose-regulated protein (Grp78), tribbles pseudokinase 3 (TRB3), and activating transcription factor 4 (ATF4) and of CCAAT/enhancer-binding protein homologous protein (CHOP), ER stress-induced apoptosis marker, and found that lobeglitazone downregulated all the genes upregulated by refeeding (Figure 2B and Supplementary Figure 2)
Summary
Non-alcoholic fatty liver disease (NAFLD), encompassing a spectrum from simple steatosis to non-alcoholic steatohepatitis (NASH), is associated with metabolic disorders such as obesity, type II diabetes (T2D), and insulin resistance [1,2,3]. Insulin resistance induces hepatic lipogenesis, precipitating lipid accumulation and oxidative stress in the liver [4]. SREBP-1c is positively regulated by hyperactivaiton of mechanistic target of rapamycin complex 1 (mTORC1) manifested in NAFLD, which promotes lipid synthesis [7,8,9]. Anti-lipogenic Effects of Lobeglitazone on NAFLD stress in the liver. Recent studies have revealed that targeting of hepatic lipogenesis is a prospective therapeutic strategy for the treatment of NAFLD [10]
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