The AGEs-RAGE axis and nonalcoholic steatohepatitis: the evidence mounts

Abstract

I read with great interest the recent article by Kimura et al. [1] about the effects of atorvastatin treatment on advanced glycation end products (AGEs) in patients with nonalcoholic steatohepatitis (NASH). The authors elegantly demonstrated that atorvastatin given at 10 mg daily for 12 months successfully reduced glyceraldehyde-derived AGEs while improving the steatosis grade and nonalcoholic fatty liver disease (NAFLD) activity score. These results suggest a crucial role for AGEs in the pathogenesis of NASH and open an avenue for AGEs-targeted treatment of one of the top three leading causes of cirrhosis. One of the major shortcomings of the study by Kimura, however, was the failure to clarify and discuss the potential role played by the receptor for advanced glycation end products (RAGE) in their findings. Previous studies have shown that interactions between AGEs and RAGE can promote a number of adverse physiologic pathways, such as oxidative stress, inflammation, and insulin resistance [2–4], all of which have been implicated in the development of NASH. Conversely, circulating soluble isoforms of RAGE (sRAGE) can inhibit RAGE-induced activation of these pathways [5, 6], and therefore, sRAGE could conceivably protect against the development of NAFLD and NASH. In fact, we have previously examined the relationship between circulating levels of sRAGE and NAFLD in humans and demonstrated that levels of sRAGE are highly reduced in the setting of NASH and inversely correlated with ALT and AST [7]. Previous studies have also clearly shown that atorvastatin can influence the expression of sRAGE and cell-bound RAGE both in vitro and in vivo [8–11]. Beside RAGE, AGEs bind to other receptors, including macrophage scavenger receptors I and II, including CD36 [12]. Interestingly, Greco et al. [13] have demonstrated that CD36 is one of the most important genes found to be upregulated in subjects with high liver fat content. Taken together, the AGEs-RAGE axis is emerging as a core piece in the pathophysiology of insulin resistance, NAFLD and NASH, and evidence suggests that atorvastatin may influence not only AGEs, but also sRAGE. Kimura et al. are to be congratulated for their important piece of work expanding the current knowledge on the role of AGEs in NASH. Regrettably, however, the paper offers only a partial insight on this issue as the potential mediating role of sRAGE on the authors’ findings was not addressed. Future studies in the field should not ignore this important point.