AMPK/mTOR pathway significance in healthy liver and non‐alcoholic fatty liver disease and its progression

Abstract

Obesity is related to several organs, but the liver is particularly affected. Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor and regulator of liver lipid dysfunction and glucose metabolism. The mechanistic target of rapamycin (mTOR) is a protein kinase regulating cell growth, survival, metabolism, and immunity. Together, these pathways are involved in obesity, insulin resistance, non-alcoholic fatty liver disease (NAFLD) and its progression, and autophagy. During energy demand, liver kinase B (LKB) phosphorylation helps activate the AMPK/mTOR pathways. Likewise, the protein forkhead box O family (FOXO) negatively regulates adipogenesis by binding to the promoter sites of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha, initiating adipogenesis. In addition, acetyl-CoA carboxylase, which regulates de novo lipogenesis, is linked to LKB and FOXO in developing NAFLD. The kinase complex, consisting of Unc-51-like autophagy-activating kinase 1 or 2 (ULK1, ULK2) by stimulating autophagy, and eliminating fat droplets in NAFLD, is regulated by mTORC1 and negatively regulated by AMPK that suppresses liver lipogenesis and increases fatty acid oxidation. Also, ULK1 is essential for initiating phagophore formation, establishing macrophagy, and generating autophagosomes. The selective breakdown of lipid droplets through macroautophagy, or macrolipophagy, occurs on a cellular energy level using free fatty acids. In addition, mTORC1 promotes lipogenesis by activating sterol regulatory element-binding protein. Finding new components and novel regulatory modes in signaling is significant for a better understanding of the AMPK/mTOR pathways, potentially facilitating the development of future diagnostic and therapeutic strategies for NAFLD and its progression to non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma.IA Marcondes-de-Castro et al.

Effects of In Utero PFOS Exposure on Epigenetics and Metabolism in Mouse Fetal Livers

“…However, there were no significant changes in the expression level of the rate-limiting enzyme, Cpt1 for mitochondrial β-oxidation (Figure C, right panel). Nevertheless, the dysregulation of mTOR/AMPK and of PPARγ pathways was linked with the progression of NAFLD …”

“…Nevertheless, the dysregulation of mTOR/AMPK and of PPARγ pathways was linked with the progression of NAFLD. 66 …”

“…Nevertheless, the dysregulation of mTOR/AMPK and of PPARγ pathways was linked with the progression of NAFLD. 66 AMPK-activation promoted glycolysis, while PPARγ regulated Retsat (retinol saturase), which is the upstream regulator of the transcriptional factor, ChREBP (the carbohydrate-responsive element binding protein), that promotes glycolysis and lipogenesis. 67,68 Our data showed significant increases in the expression levels of the glucose transporters (Glut2 and Glut4) (Figure 4D, left panel), which might support glucose utilization in PFOS-induced metabolic disturbances.…”

Unveiling global research trends and hotspots on mitochondria in NAFLD from 2000 to 2023: A bibliometric analysis

“…Because of its crucial role in lipid metabolism, mTORC1 signaling contributes to the inhibition of liver lipophagy by promoting lipogenesis. 62 The regulation of autophagy is influenced by various factors, such as amino acids, insulin, and the mTOR signaling pathways, which can either inhibit or promote autophagy. Due to its pivotal role, autophagy assumes a central position in the regulation of liver physiology and the maintenance of hepatic metabolism.…”

Metformin: update on mechanisms of action on liver diseases

“…103 In fasting, Metformin increases AMPK activity, which increases the activity of LXR-α. LXR-α then suppresses sterol regulatory element binding protein-1c (SREBP-1c, a master regulator of liver lipogenesis gene programme), which in turn suppresses enzymes of lipogenesis [ACC1, fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1)], thereby inhibiting lipogenesis ( 22 ). AMPK can also directly inhibit ACC2, decrease malonyl Co-A, and activate carnitine palmitoyl transferase 1 (CPT1), and thereby enhancing β-oxidation.…”