Meaurement of advanced glycation end products may change NASH managment

Haemoglobin A1c was the first product of glycation reactions to be discovered in the late 1960s. It caused revolutionary changes to the management of diabetes. What was thought to be an artifact of hemoglobin electrophoresis turned out to be the most reliable index of disease progression in patients with diabetes. After that, the discovery of nonenzymatic advanced glycation end products (AGEs) and receptors of AGE (RAGE) opened up a new avenue of research; and interest in the Maillard reaction has been growing rapidly over the past few decades.

Nowadays, advanced glycation end products are considered to be markers of oxidative stress. They seem to be involved in the atherosclerotic process and progression of long-term diabetes complications, including microvascular and macrovascular dysfunction. Apart from diabetes-associated diseases, a role for increased circulating levels of AGEs and decreased serum and tissue RAGE has been claimed in the pathogenesis of a number of different diseases,¹ and they are also likely to play a major role in the pathogenesis of vessel damage occurring in patients with non-alcoholic fatty liver disease (NAFLD), thus contributing to the increased cardiovascular risk observed in these patients.²

In this issue of the Journal, Hyogo et al.³ move beyond the fascinating and intuitive hypothesis that AGEs and their receptors may act also in the pathogenesis and progression of NAFLD. More importantly, the authors suggest that measurement of circulating AGEs may be a useful clinical tool for discriminating patients with non-alcoholic steatohepatitis (NASH), given that such patients show increased levels of AGEs as compared with patients with simple steatosis, and that AGEs correlate negatively with adiponectin (a marker of insulin sensitivity) and positively with value of insulin resistance (IR). Although several caveats render inconsistent the clinical values of AGEs in the diagnosis of the disease, e.g. the low sensitivity of the most toxic glycer-AGE in predicting NASH or the lack of an external validation, the rationale supporting the authors' hypotheses remains basically very simple and elegant. Both insulin resistance and oxidative stress contribute to the progression from simple to complicated NAFLD.^4–6 So far, reactive oxygen species (ROS) are implied in NASH pathogenesis; however, it has also been suggested that oxidative stress, through the production of ROS, underlies the development of IR, beta-cell dysfunction, impaired glucose tolerance, and type 2 diabetes mellitus.⁷ AGEs are products of oxidative stress as well, and nonenzymatically glycation is the major source of ROS, through generation of superoxide, hydroxyl group, and hydrogen peroxide.^8,9 Glycation reactions occur in vivo as in vitro inducing oxidative chemical modifications of several compounds, including proteins, DNA, and lipids. Carboxymethyllysine is a product of lipid oxidation.¹⁰ In the context of NAFLD and IR, the availability of fatty acids provides substrate to the liver to increase lipid oxidation, thus generating ROS and AGEs. The interaction of AGEs with RAGE may lead glucose-uptake to worsen, particularly through the over-generation of intracellular ROS.¹¹ Insulin resistance may be additionally due to different mechanisms. Glycation reaction inactivates several enzymes and hormones including insulin.¹² Binding of modified insulin with its receptor may not properly activate the insulin cascade signaling. Finally, AGEs can impair insulin secretion,⁷ and in this case, increased IR may represent a compensatory consequence. On the other hand, preferential impairment of non-oxidative glucose metabolism causes, in a vicious cycle, the intracellular formation of AGEs, oxidative stress, and activation of other pathogenic mediators¹³ such as interleukins and TNF-α. TNF-α levels and AGEs correlate positively. Patients with NASH show higher levels of TNF-α than subjects with simple steatosis.¹⁴ Furthermore, AGEs are able to recruit macrophages and monocytes.¹⁵ Through the binding to RAGE on these cells as well as on hepatocytes,¹⁶ they activate the nuclear transcription factor NF-κB, a key enzyme involved in inflammatory processes, activity of innate immune system, and IR.

In conclusion, AGEs, as well as ROS, causing insulin resistance and inflammation, are commonly involved in the development of a number of metabolic diseases. Caloric restriction represents the first line for all these diseases. Excess nourishment and sedentary lifestyle result in production of ROS and AGEs; and vice versa, calorie restraint in animal models and humans reduces insulin resistance, low-grade inflammation,¹⁷ and ameliorate liver function and histology in NASH patients,¹⁸ likely through the significant reduction of reactive products. The question raised is whether the determination of AGEs and ROS can represent a diagnostic tool for evaluating whole-body wellness and monitoring therapy in low-grade inflammatory- and IR-related diseases, including, of course, NASH. Although great effort has been put into this area of research, much remains to be done, including the detection and characterization of the possible roles of these molecules in the progression of NAFLD to NASH and cirrhosis.