Pathological Consequences of Hepatic mTORC1 Dysregulation

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of metabolism that integrates environmental inputs, including nutrients, growth factors, and stress signals. mTORC1 activation upregulates anabolism of diverse macromolecules, such as proteins, lipids, and nucleic acids, while downregulating autolysosomal catabolism. mTORC1 dysregulation is often found in various diseases, including cancer, cardiovascular and neurodegenerative diseases, as well as metabolic syndromes involving obesity and type II diabetes. As an essential metabolic organ, the liver requires proper regulation of mTORC1 for maintaining homeostasis and preventing pathologies. For instance, aberrant hyper- or hypoactivation of mTORC1 disrupts hepatocellular homeostasis and damages the structural and functional integrity of the tissue, leading to prominent liver injury and the development of hepatocellular carcinogenesis. Proper regulation of mTORC1 during liver diseases may be beneficial for restoring liver function and ameliorating the detrimental consequences of liver failure.

Keywords: liver; mTORC1; metabolism.

Figure 1

Upstream and downstream of mTORC1 signaling. mTORC1 is regulated by hormone, growth factor, stress, and nutrient signaling. Through signaling mediators, such as Sestrins, TSC, and GATOR1 protein complexes, mTORC1 activity is delicately modulated in cells. Active mTORC1 kinase phosphorylates various substrates to regulate cell metabolism. Red-highlighted genes were mutated in livers to understand the hepatocellular role of mTORC1.

Figure 2

Consequences of mTORC1 dysregulation. Proper regulation of mTORC1 activity is critical for homeostatic maintenance of liver metabolism. Hypo- or hyper-activation of mTORC1 can provoke metabolic dysregulation and oxidative stress, which can lead to hepatocyte injury, inflammation, and subsequent hepatocarcinogenesis.