Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems.

Advanced glycation endproducts (AGEs) are involved in several diseases, including NAFLD and NASH. RAGE is the main receptor mediating the pro-inflammatory signalling induced by AGEs. Therefore, targeting of RAGE has been proposed for prevention of chronic inflammatory diseases. However, the role of RAGE in the development of NAFLD and NASH remains poorly understood. We thus aimed to analyse the effect of obesity on AGEs accumulation, AGE-receptors and AGE-detoxification, and whether the absence of RAGE might improve hepatosteatosis and inflammation, by comparing the liver of lean control, obese (LeptrDb-/-) and obese RAGE-deficient (RAGE-/- LeptrDb-/-) mice. Obesity induced AGEs accumulation and RAGE expression with hepatosteatosis and inflammation in LeptrDb-/-, compared to lean controls. Despite the genetic deletion of RAGE in the LeptrDb-/- mice, high levels of intrahepatic AGEs were maintained accompanied by decreased expression of the protective AGE-receptor-1, impaired AGE-detoxifying system glyoxalase-1, and increased expression of the alternative AGE-receptor galectin-3. We also found sustained hepatosteatosis and inflammation as determined by persistent activation of the lipogenic SREBP1c and proinflammatory NLRP3 signalling pathways. Thus, RAGE targeting is not effective in the prevention of NAFLD in conditions of obesity, likely due to the direct liver specific crosstalk of RAGE with other AGE-receptors and AGE-detoxifying systems.

Fatty liver--based identification of two distinct hypertriglyceridemic subgroups in familial combined hyperlipidemia.

The present study was conducted to investigate whether the fatty liver phenotype could be helpful in the identification of subgroups with distinct metabolic properties and lipid profiles within familial combined hyperlipidemia (FCHL). One hundred eighty-five FCHL family members participated in the current study; 38 subjects were found to be hypertriglyceridemic, of whom 66% showed evidence of fatty liver as measured with ultrasound. A detailed comparison between the hypertriglyceridemic FCHL subjects with (n = 25) and without (n = 13) fatty liver revealed that, despite very similar plasma triglyceride levels (3.5 vs 3.2 mmol/L in subjects with and without fatty liver, respectively), the fatty liver subgroup presented with significantly higher body mass index, visceral adipose tissue (ultrasound), insulin, and alanine aminotransferase levels. Moreover, very low-density lipoprotein (VLDL) subclass analysis showed that the VLDL2 fraction of the fatty liver subgroup contained significantly less cholesterol and triglycerides (P = .02 for both parameters), which was likely explained by a decreased VLDL2 particle number because VLDL2 apolipoprotein B levels tended to be lower (P = .08). These data indicate that hypertriglyceridemic FCHL subjects may belong to metabolically distinct subgroups and suggest that a refinement of the hypertriglyceridemic FCHL phenotype by adding information on fatty liver will eventually facilitate the elucidation of its complex genetic background.