Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease

Abstract

AIMTo determine if manipulation of dietary advanced glycation end product (AGE), intake affects non-alcoholic fatty liver disease (NAFLD) progression and whether these effects are mediated via RAGE.METHODSMale C57Bl6 mice were fed a high fat, high fructose, high cholesterol (HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mRNA were determined.RESULTSLong-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content (a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE-/- animals developed NASH of similar severity to RAGE+/+ animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury.CONCLUSIONIn the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.

Caffeic acid attenuates the inflammatory stress induced by glycated LDL in human endothelial cells by mechanisms involving inhibition of AGE‐receptor, oxidative, and endoplasmic reticulum stress

“…8. Published data show that besides diabetes and atherosclerosis, RAGE, and/or ERS contribute to the pathogenesis of various diseases, such as nonalcoholic fatty liver disease, different types of cancer or neurodegenerative diseases, amyotrophic lateral sclerosis, and prion disease [42][43][44][45]. Thus, our results indicate that CAF, a natural product present in various concentrations in the regular diets, could ameliorate a wide spectrum of disorders.…”

Hepatic microvascular dysfunction and increased advanced glycation end products are components of non-alcoholic fatty liver disease

“…Similarly, Hyogo et al, 2007 showed that AGE levels were significantly elevated in NASH patients compared to those with simple steatosis, however the AGE levels were no different with the steatosis grade of those patients [13]. Leung et al (2016) showed similar results using high-AGE diet induced experimental NAFLD [16]. According to the multiple hit hypothesis of NASH progression several parallel factors synergistically contribute to disease progression from benign steatosis to steatohepatitis [53,54].…”

Beneficial effect of apple vinegar on reproductive parameters in male rat model of nonalcoholic fatty liver disease

“…NAFLD is a disease that occurs with excessive fat accumulation in the liver without excessive alcohol consumption. It is closely correlated with both diabetes and obesity (Leung et al., ). Ye et al.…”