Involvement of Intracellular TAGE and the TAGE–RAGE–ROS Axis in the Onset and Progression of NAFLD/NASH

Abstract

The repeated excessive intake of sugar, a factor that contributes to the onset of nonalcoholic fatty liver disease (NAFLD) and its progression to the chronic form of nonalcoholic steatohepatitis (NASH), markedly increases the hepatocyte content of glyceraldehyde (GA), a glucose/fructose metabolic intermediate. Toxic advanced glycation end-products (toxic AGEs, TAGE) are synthesized by cross-linking reactions between the aldehyde group of GA and the amino group of proteins, and their accumulation has been implicated in the development of NAFLD/NASH and hepatocellular carcinoma (HCC). Our previous findings not only showed that hepatocyte disorders were induced by the intracellular accumulation of TAGE, but they also indicated that extracellular leakage resulted in elevated TAGE concentrations in circulating fluids. Interactions between extracellular TAGE and receptor for AGEs (RAGE) affect intracellular signaling and reactive oxygen species (ROS) production, which may, in turn, contribute to the pathological changes observed in NAFLD/NASH. RAGE plays a role in the effects of the extracellular leakage of TAGE on the surrounding cells, which ultimately promote the onset and progression of NAFLD/NASH. This review describes the relationships between intracellular TAGE levels and hepatocyte and hepatic stellate cell (HSC) damage as well as the TAGE–RAGE–ROS axis in hepatocytes, HSC, and HCC cells. The “TAGE theory” will provide novel insights for future research on NAFLD/NASH.

Structures of Toxic Advanced Glycation End-Products Derived from Glyceraldehyde, A Sugar Metabolite

“…Previous studies have suggested the involvement of TAGE accumulation in the pathogenesis of NASH, CVD, DM and its complications, some cancer types, and AD [22,23,[37][38][39]55,77]. We recently demonstrated that TAGE were produced by and accumulated in many cell types [24][25][26][27][28][29][30][31][32][33][34][35][36].…”

“…The formation of TAGE mainly occurs intracellularly through glycation reactions between GA and intracellular proteins, which produce TAGE molecules of different sizes and properties. Although a more detailed understanding of the mechanisms underlying TAGE toxicity is needed, previous studies have indicated that it is due to oxidative stress-induced damage [26,39], the loss of protein functions as a result of glycation modifications [39], and TAGE aggregation and accumulation [30].…”

“…These findings indicate that the production and accumulation of intracellular TAGE induce cell damage and inflammatory reactions. Therefore, strategies to suppress the intracellular accumulation of TAGE have potential for the prevention and treatment of the onset/progression of NASH [39].…”

“…In our recent studies, we showed that intracellularly accumulated GA-AGEs contributed to the onset/progression of lifestyle-related diseases (LSRDs) by triggering cell Biomolecules 2024, 14, 202 2 of 15 damage [24][25][26][27][28][29][30][31][32][33][34][35][36]. Elevated intracellular levels of GA-AGEs have also been implicated in the pathogenesis of metabolic syndrome (MetS), non-alcoholic steatohepatitis (NASH), cardiovascular diseases (CVD), diabetes mellitus (DM) and its complications, some cancer types, and Alzheimer's disease (AD) [22,23,[37][38][39]. Although the mechanisms by which GA-AGEs exert their toxic effects and the specific structures responsible have not yet been elucidated, previous studies have demonstrated that an antibody targeting GA-AGEs can effectively attenuate AGE-induced neurotoxicity in the serum of patients with diabetic nephropathy with hemodialysis (DN-HD) [40].…”

Wheat germ peptides improving liver aging damage in rats through the AMPK/SIRT1 pathway

“…(DNA-damage response, DDR), 在转录水平激活P53, 导致细胞衰老, 因此P53被视作衰老的生物标志物 [24] . 衰老过程中伴随产生的氧化应激是引起肝脏损 伤, 导致NAFLD等肝脏疾病发病的重要因素 [30] . 氧化 应激水平过高以及抗氧化酶活性的下降会导致肝细胞 的蛋白质、脂质以及核酸降解, 从而导致肝脏损伤 [31] .…”