RAGE deficiency does not affect non-alcoholic steatohepatitis and atherosclerosis in Western type diet-fed Ldlr−/− mice

Abstract

Non-alcoholic fatty liver disease is a spectrum of liver diseases ranging from steatosis only to non-alcoholic steatohepatitis (NASH). The latter is characterized by hepatic inflammation, which increases the risk of cardiovascular disease. It is poorly understood which factors contribute to the onset of hepatic inflammation characterizing the progression from steatosis to NASH. Previously, we demonstrated increased advanced glycation endproducts (AGEs) in the livers of NASH patients. We hypothesise that AGEs play a key role in NASH development by activating their proinflammatory receptor, RAGE. RAGE-deficient mice and wildtype littermates, both on Ldlr−/− background, were fed a Western type diet (WTD) for 3 or 12 weeks. Flow cytometry, histology, gene expression and AGE measurements were performed to evaluate the effects of RAGE deficiency. RAGE-deficient mice displayed reduced weight gain and visceral fat expansion compared to control mice. No difference in adipose tissue inflammation was observed between groups. RAGE deficiency did not affect WTD-induced monocytosis, circulating lipids or hepatic steatosis. WTD-induced hepatic neutrophil and macrophage accumulation and atherosclerotic plaque development was comparable between control and RAGE-deficient mice. No difference in AGE levels was observed. RAGE does not seem to play a major role in the development of NASH or atherosclerosis in a hyperlipidemic mouse model.

Aging‐induced aberrant RAGE/PPARα axis promotes hepatic steatosis via dysfunctional mitochondrial β oxidation

“…Thus, although we could not completely rule out the possibility that the PKA signaling inactivation participates in the protective effects of RAGE deficiency on the liver of aging mice, the role of this signaling is limited. Bijnen et al (2018) claimed that RAGE-deficient mice displayed reduced weight gain and visceral fat expansion compared to control mice and RAGE does not play a major role in the development of NASH in a hyperlipidemic mouse model. Currently, although the reason for this inconsistency is unclear, the animal models and feeding conditions were different in the two studies.…”

“…Therefore, all these data indicate a critical role of RAGE in the regulation of hepatic steatosis. However, a recent study claimed that RAGE‐deficient mice displayed reduced weight gain and visceral fat expansion compared to control mice and RAGE does not play a major role in the development of NASH in a hyperlipidemic mouse model (Bijnen et al, 2018). As RAGE is widely expressed, the whole‐body deletion of RAGE might differ from the liver‐specific suppression of RAGE.…”

The Receptor for Advanced Glycation Endproducts (RAGE) Contributes to Severe Inflammatory Liver Injury in Mice

“…This receptor is also expressed on hepatic stellate cells, epithelial hepatocytes and Kupffer cells (19,20). However, its contribution to inflammatory liver disease is still an unresolved issue (21).…”

Increase of α-dicarbonyls in liver and receptor for advanced glycation end products on immune cells are linked to nonalcoholic fatty liver disease and liver cancer

“… 54 In particular, plasma and liver levels of MGO were increased in RAGE −/− mice fed with a Western-type diet. 55 Also, it has been shown that HFD was associated with increased AGE levels in the liver, heart, and kidney of rats. 56 …”

“…54 In particular, plasma and liver levels of MGO were increased in RAGE −/− mice fed with a Western-type diet. 55 Also, it has been shown that HFD was associated with increased AGE levels in the liver, heart, and kidney of rats. 56 The role of AGEs, RAGE, and particularly their interaction has been in focus last decades due to the potential regulation of the NF-κB inflammatory pathway by AGE-RAGE.…”