The Antidiabetic Drug Lobeglitazone Protects Mice From Lipogenesis-Induced Liver Injury via Mechanistic Target of Rapamycin Complex 1 Inhibition

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.

TorS ‐ Reframing a rational for type 2 diabetes treatment

“…83 Indeed, similar to metformin, TZDs are reported to inhibit mitochondrial complex I, [88][89][90][91] resulting in AMPK activation, 92 and suppression of mTORC1 kinase activity. [93][94][95][96][97][98] Thus, the suppression of hyperactive mTORC1 by TZDs may account for their apparent insulin-sensitising activity, resulting in glycaemic control while suppressing insulin secretion. Also, the suppression of hyperactive mTORC1 by TZDs may drive cardio-renal and beta-cell autophagy and mitophagy, 99 thereby counteracting diabetic cardiomyopathy, nephropathy and beta-cell failure.…”

“…Indeed, similar to metformin, TZDs are reported to inhibit mitochondrial complex I, 88–91 resulting in AMPK activation, 92 and suppression of mTORC1 kinase activity 93–98 . Thus, the suppression of hyperactive mTORC1 by TZDs may account for their apparent insulin‐sensitising activity, resulting in glycaemic control while suppressing insulin secretion.…”

Lobeglitazone: A Novel Thiazolidinedione for the Management of Type 2 Diabetes Mellitus

“…Similar to the therapeutic effect of pioglitazone on fatty liver, lobeglitazone also attenuated hepatic steatosis in obese mice by increasing insulin sensitivity and inhibiting hepatic lipogenesis [ 16 , 17 ].…”

Normalization of the α1-Na/K-ATPase/Src Signalosome Restored Microbiota Communities and Rescinded NASH Progression in the Mouse

“…[48][49][50] Liver apoptotic activity was determined through grading five images at 40x magnification of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) stained liver slides (Figure A3C, Click-iT Plus TUNEL assay kit, Invitrogen by Thermo Fisher Scientific, MA). [51][52][53][54][55][56] Lastly, liver cellular senescence was determined by grading five images at 40x magnification of liver slides stained for β-Galactosidase activity (Figure A3D, Cell signaling Technology #9860, MA). Digitally recorded images at 40x magnification on the label (but blinded liver slides), were saved using ImageJ1.51u software.…”