Chronic administration of saturated fats and fructose differently affect SREBP activity resulting in different modulation of Nrf2 and Nlrp3 inflammasome pathways in mice liver

The overconsumption of both saturated fats and fructose in the modern society has been related to the development of nonalcoholic fatty liver disease (NAFLD). However, the specific contribution of individual dietary components on the progression of NAFLD to nonalcoholic steatohepatitis (NASH) has been poorly investigated.Therefore, the aim of our study was to investigate the dissimilar effects of these two dietary components on selected proinflammatory and antioxidant pathways in the liver of C57BL/6 mice fed a standard (SD), a 45% saturated fat (HFAT) or a 60% fructose (HFRT) diet for 12 weeks. HFAT diet evoked systemic metabolic alterations and overweight, not observed in HFRT mice. However, HFRT mice had a greater hepatic triglyceride deposition with increased ratio of triacylglycerols containing the palmitic acid compared to HFAT, as assessed by liquid chromatography-mass spectrometry analysis. This effect is due to the higher activation of the SCAP/SREBP1c lipogenic pathway by HFRT feeding. In addition, we found inhibition of Keap1/Nrf2 antioxidant signaling and more robust stimulation of the Nlrp3 inflammasome pathway in the livers of HFRT-fed mice when compared with HFAT-fed mice, which is consistent with the recent finding that palmitate and SREBP1c are implicated in hepatic oxidative stress and inflammation. These effects were associated with increased hepatic inflammation, as confirmed by high expression of markers of leukocyte infiltration in the HFRT group. Thus, we hypothesize an amplifying loop among lipogenesis, palmitate, Nrf2 and Nlrp3 that leads to a higher risk of NAFLD progression to NASH in a high-fructose diet compared to a high-saturated fat intake. (C) 2017 Elsevier Inc. All rights reserved

Heterozygous Loss of KRIT1 in Mice Affects Metabolic Functions of the Liver, Promoting Hepatic Oxidative and Glycative Stress

KRIT1 loss-of-function mutations underlie the pathogenesis of Cerebral Cavernous Malformation (CCM), a major vascular disease affecting the central nervous system (CNS). However, KRIT1 is also expressed outside the CNS and modulates key regulators of metabolic and oxy-inflammatory pathways, including the master transcription factor FoxO1, suggesting a widespread functional significance. Herein, we show that the KRIT1/FoxO1 axis is implicated in liver metabolic functions and antioxidative/antiglycative defenses. Indeed, by performing comparative studies in KRIT1 heterozygous (KRIT1+/−) and wild-type mice, we found that KRIT1 haploinsufficiency resulted in FoxO1 expression/activity downregulation in the liver, and affected hepatic FoxO1-dependent signaling pathways, which are markers of major metabolic processes, including gluconeogenesis, glycolysis, mitochondrial respiration, and glycogen synthesis. Moreover, it caused sustained activation of the master antioxidant transcription factor Nrf2, hepatic accumulation of advanced glycation end-products (AGEs), and abnormal expression/activity of AGE receptors and detoxifying systems. Furthermore, it was associated with an impairment of food intake, systemic glucose disposal, and plasma levels of insulin. Specific molecular alterations detected in the liver of KRIT1+/− mice were also confirmed in KRIT1 knockout cells. Overall, our findings demonstrated, for the first time, that KRIT1 haploinsufficiency affects glucose homeostasis and liver metabolic and antioxidative/antiglycative functions, thus inspiring future basic and translational studies

Reduced Susceptibility to Sugar-Induced Metabolic Derangements and Impairments of Myocardial Redox Signaling in Mice Chronically Fed with D-Tagatose when Compared to Fructose

Background. D-tagatose is an isomer of fructose and is ~90% as sweet as sucrose with less caloric value. Nowadays, D-tagatose is used as a nutritive or low-calorie sweetener. Despite clinical findings suggesting that D-tagatose could be beneficial in subjects with type 2 diabetes, there are no experimental data comparing D-tagatose with fructose, in terms of metabolic derangements and related molecular mechanisms evoked by chronic exposure to these two monosaccharides. Materials and methods. C57Bl/6j mice were fed with a control diet plus water (CD), a control diet plus 30% fructose syrup (L-Fr), a 30% fructose solid diet plus water (S-Fr), a control diet plus 30% D-tagatose syrup (L-Tg), or a 30% D-tagatose solid diet plus water (S-Tg), during 24 weeks. Results. Both solid and liquid fructose feeding led to increased body weight, abnormal systemic glucose homeostasis, and an altered lipid profile. These effects were associated with vigorous increase in oxidative markers. None of these metabolic abnormalities were detected when mice were fed with both the solid and liquid D-tagatose diets, either at the systemic or at the local level. Interestingly, both fructose formulations led to significant Advanced Glycation End Products (AGEs) accumulation in mouse hearts, as well as a robust increase in both myocardial AGE receptor (RAGE) expression and NF-κB activation. In contrast, no toxicological effects were shown in hearts of mice chronically exposed to liquid or solid D-tagatose. Conclusion. Our results clearly suggest that chronic overconsumption of D-tagatose in both formulations, liquid or solid, does not exert the same deleterious metabolic derangements evoked by fructose administration, due to differences in carbohydrate interference with selective proinflammatory and oxidative stress cascades

Fructose liquid and solid formulations differently affect gut integrity, microbiota composition and related liver toxicity: a comparative in vivo study

Despite clinical findings suggesting that the form (liquid versus solid) of the sugars may significantly affect the development of metabolic diseases, no experimental data are available on the impact of their formulations on gut microbiota, integrity and hepatic outcomes. In the present sudy, C57Bl/6j mice were fed a standard diet plus water (SD), a standard diet plus 60% fructose syrup (L-Fr) or a 60% fructose solid diet plus water (S-Fr) for 12 weeks. Gut microbiota was characterized through 16S rRNA phylogenetic profiling and shotgun sequencing of microbial genes in ileum content and related volatilome profiling. Fructose feeding led to alterations of the gutmicrobiota depending on the fructose formulation,with increased colonization by Clostridium,Oscillospira and Clostridiales phyla in the S-Fr group and Bacteroides, Lactobacillus, Lachnospiraceae and Dorea in the L-Fr. S-Fr evoked the highest accumulation of advanced glycation end products and barrier injury in the ileum intestinal mucosa. These effects were associated to a stronger activation of the lipopolysaccharide-dependent proinflammatory TLR4/NLRP3 inflammasomepathway in the liver of S-Fr mice than of L-Fr mice. In contrast, L-Fr intake induced higher levels of hepatosteatosis andmarkers of fibrosis than S-Fr. Fructoseinduced ex novo lipogenesis with production of SCFA and MCFA was confirmed by metagenomic analysis. These results suggest that consumption of fructose under different forms, liquid or solid, may differently affect gut microbiota, thus leading to impairment in intestinal mucosa integrity and liver homeostasis