Trefoil Factor 3 Deficiency Affects Liver Lipid Metabolism

Abstract

Background/Aims: Tff3 protein plays a well recognized role in the protection of gastrointestinal mucosa. The role of Tff3 in the metabolism is a new aspect of its function. Tff3 is one of the most affected liver genes in early diabetes and fatty liver rodent models. The aim of this study was to investigate the effect of Tff3 deficiency on lipid and carbohydrate metabolism and on markers of oxidative stress that accompanies metabolic deregulation. Methods: Specific markers of health status were determined in sera of Tff3 deficient mice, including glucose level, functional glucose and insulin tolerance. Composition of fatty acids (FAs) was determined in liver and blood serum by using gas chromatography. Oxidative stress parameters were determined: lipid peroxidation level via determination of lipid hydroperoxide and thiobarbituric acid reactive substances (TBARS), antioxidative capacity (FRAP) and specific antioxidative enzyme activity. The expression of several genes and proteins related to the metabolism of lipids, carbohydrates and oxidative stress (CAT, GPx1, SOD2, PPARα, PPARγ, PPARδ, HNF4α and SIRT1) was determined. Results: Tff3 deficient mice showed better glucose utilization in the glucose and insulin test. Liver lipid metabolism is affected and increased formation of small lipid vesicles is noticed. Formation of lipid droplets is not accompanied by increased liver oxidative stress, although expression/activity of monitored enzymes is deregulated when compared with wild type mice. Tff3 deficient mice exhibit reduced expression of metabolism relevant SIRT1 and PPARγ genes. Conclusion: Tff3 deficiency affects the profile and accumulation of FAs in the liver, with no obvious oxidative stress increase, although expression/activity of monitored enzymes is changed as well as the level of SIRT1 and PPARγ protein. Considering the strong downregulation of liver Tff3 in diabetic/obese mice, presence in circulation and regulation by food/insulin, Tff3 is an interesting novel candidate in metabolism relevant conditions.

Effect of Tff3 Deficiency and ER Stress in the Liver

“…This finding is consistent with results from a former study where Guillén et al showed a decreased Tff3 gene expression in mice with a stronger extent of liver steatosis [18]. Our findings in the liver of mixed background Tff3 −/− mice on a normal diet show that fat vacuole formation was also affected [35]. Ultrastructural analysis of the liver tissues show no difference in a number of immunologically relevant cells, and no difference in the general morphology of mitochondria, hepatocyte cell bodies, cytoplasm or capillaries between Tm-treated Tff3 −/− mice and Wt control mice.…”

“…Tff3 −/− Tm-treated mice have a slightly but significantly higher expression level of GPX1 (1.35 fold) relative to Wt Tm-treated mice (Figure 3B). Previous reports showed no significant difference in liver GPX1 expression between WT and Tff3 −/− mice of mixed background in control condition similar as in this new strain background [35]. GPX activity in NAFLD livers compared to control is significantly higher [36] and the severity of disease is correlated with the decreased activity of GPX [37].…”

Leukocyte Activation and Antioxidative Defense Are Interrelated and Moderately Modified by n-3 Polyunsaturated Fatty Acid-Enriched Eggs Consumption—Double-Blind Controlled Randomized Clinical Study

“…Profiling of plasma fatty acids concentrations was done in the Radiation Chemistry and Dosimetry Laboratory, Division of Materials Chemistry, Ruđer Bošković Institute (IRB), Zagreb, Croatia, according to previously described protocol [ 21 ]. Total lipids were extracted from plasma and treated with 0.5 M KOH/MeOH (Merck, Germany) to induce formation of the fatty acid methyl esters (FAMEs).…”

“…Individual fatty acids were determined in plasma samples and expressed as relative percentages of FAME obtained from total lipid extract. The percentage of FAME (a relative amount of each fatty acid) was quantified by integrating the area under the peak and dividing the results by the total area for all fatty acids [ 21 ].…”

Impact of High Salt Diet on Cerebral Vascular Function and Stroke in Tff3−/−/C57BL/6N Knockout and WT (C57BL/6N) Control Mice

“…Genetically modified mice are frequently used stroke models for studying the molecular pathophysiology of stroke [15,16,17,18]. The Tff3 −/− / C57BL/6N ( Tff3 ) knockout mice model represents a promising new model for studying vascular function, atherosclerotic lesions, and the synthesis of proinflammatory cytokines due to altered lipid metabolism [19,20]. The metabolites of arachidonic acid (AA) have a significant role in mediating vascular reactivity to various stimuli, affecting tissue perfusion and supply, and exerting proinflammatory or anti-inflammatory effects on vessels and other tissues [21].…”