Effect of Tff3 Deficiency and ER Stress in the Liver

Šešelja, Kate; Bazina, Iva; Welss, Jessica; Schicht, Martin; Paulsen, Friedrich; Bijelić, Nikola; Rođak, Edi; Horvatić, Anita; Gelemanović, Andrea; Mihalj, Martina; Lončar, Mirela Baus

doi:10.3390/ijms20184389

Cited by 8 publications

(8 citation statements)

References 69 publications

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“…It protects the intestinal mucosa from various injuries and facilitates mucosal restitution by promoting cell migration and inhibiting apoptosis ( 68 , 69 ). TFF3 is also expressed in the liver, pancreas, and brain ( 57 , 70 , 71 ). Intracerebral and i.p.…”

Section: Discussionmentioning

confidence: 99%

Intestinal activating transcription factor 4 regulates stress-related behavioral alterations via paraventricular thalamus in male mice

Guo

Zhou

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Chronic stress induces depression- and anxiety-related behaviors, which are common mental disorders accompanied not only by dysfunction of the brain but also of the intestine. Activating transcription factor 4 (ATF4) is a stress-induced gene, and we previously show that it is important for gut functions; however, the contribution of the intestinal ATF4 to stress-related behaviors is not known. Here, we show that chronic stress inhibits the expression of ATF4 in gut epithelial cells. ATF4 overexpression in the colon relieves stress-related behavioral alterations in male mice, as measured by open-field test, elevated plus-maze test, and tail suspension test, whereas intestine-specific ATF4 knockout induces stress-related behavioral alterations in male mice. Furthermore, glutamatergic neurons are inhibited in the paraventricular thalamus (PVT) of two strains of intestinal ATF4-deficient mice, and selective activation of these neurons alleviates stress-related behavioral alterations in intestinal ATF4-deficient mice. The highly expressed gut-secreted peptide trefoil factor 3 (TFF3) is chosen from RNA-Seq data from ATF4 deletion mice and demonstrated decreased in gut epithelial cells, which is directly regulated by ATF4. Injection of TFF3 reverses stress-related behaviors in ATF4 knockout mice, and the beneficial effects of TFF3 are blocked by inhibiting PVT glutamatergic neurons using DREADDs. In summary, this study demonstrates the function of ATF4 in the gut–brain regulation of stress-related behavioral alterations, via TFF3 modulating PVT neural activity. This research provides evidence of gut signals regulating stress-related behavioral alterations and identifies possible drug targets for the treatment of stress-related behavioral disorders.

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Section: Discussionmentioning

confidence: 99%

Intestinal activating transcription factor 4 regulates stress-related behavioral alterations via paraventricular thalamus in male mice

Guo

Zhou

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…In contrast, TFF3 deficiency impairs fatty-acid distribution and accumulation in mouse liver, showing reduced expression of metabolism-related genes and increased number of small lipid vesicles [33,34], raising the possibility that TFF3 affects hepatic lipid-droplet formation. Conversely, intraperitoneal injection of recombinant TFF3 protein or tail-vein injection of adenovirusmediated TFF3 overexpression ameliorated several indicators associated with NAFLD in diabetic (db/db), obese (ob/ob), and diet-induced obese mice or rats, possibly by mediating hepatic fatty-acid oxidation via increasing peroxisome proliferatoractivated receptor-α levels [19] (Fig.…”

Section: Pathological Effects Of Tff3 In Disease Tff3 In T2dmmentioning

confidence: 99%

“…Acute endoplasmic reticulum stress Decreased ability for pro-inflammatory cascade initiation. [34] Nervous system research High-salt diet combined with transient occlusion of middle cerebral artery Stroke TFF3 depletion impaired vascular function and worsened stroke outcomes.…”

Section: Injection Of Tunicamycinmentioning

confidence: 99%

Pathological and therapeutic roles of bioactive peptide trefoil factor 3 in diverse diseases: recent progress and perspective

Yang

Lin

et al. 2022

Cell Death Dis

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Trefoil factor 3 (TFF3) is the last small-molecule peptide found in the trefoil factor family, which is mainly secreted by intestinal goblet cells and exerts mucosal repair effect in the gastrointestinal tract. Emerging evidence indicated that the TFF3 expression profile and biological effects changed significantly in pathological states such as cancer, colitis, gastric ulcer, diabetes mellitus, non-alcoholic fatty liver disease, and nervous system disease. More importantly, mucosal protection would no longer be the only effect of TFF3, it gradually exhibits carcinogenic activity and potential regulatory effect of nervous and endocrine systems, but the inner mechanisms remain unclear. Understanding the molecular function of TFF3 in specific diseases might provide a new insight for the clinical development of novel therapeutic strategies. This review provides an up-to-date overview of the pathological effects of TFF3 in different disease and discusses the binding proteins, signaling pathways, and clinical application.

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“…This study aimed to determine the effect of Tff3 deficiency on the intestines of male and female mice under metabolically relevant conditions of long-term consumption of a high-fat diet (HFD) known to have pathological effects on the GLB axis. To exclude the effects of additional mutations and mixed genetic variations, we used a new congenic Tff3-/strain on the C57BL/6NCrl genetic background with no additional metabolismrelevant mutations [24]. As existing data link Tff3 to metabolism, it is of great interest to investigate the systemic role of Tff3 deficiency in long-term HFD feeding (36 weeks).…”

Section: Introductionmentioning

confidence: 99%

Tff3 Deficiency Differentially Affects the Morphology of Male and Female Intestines in a Long-Term High-Fat-Diet-Fed Mouse Model

Šešelja,

Bazina,

Vrecl

et al. 2023

IJMS

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Trefoil factor family protein 3 (Tff3) protects the gastrointestinal mucosa and has a complex mode of action in different tissues. Here, we aimed to determine the effect of Tff3 deficiency on intestinal tissues in a long-term high-fat-diet (HFD)-fed model. A novel congenic strain without additional metabolically relevant mutations (Tff3-/-/C57Bl6NCrl strain, male and female) was used. Wild type (Wt) and Tff3-deficient mice of both sexes were fed a HFD for 36 weeks. Long-term feeding of a HFD induces different effects on the intestinal structure of Tff3-deficient male and female mice. For the first time, we found sex-specific differences in duodenal morphology. HFD feeding reduced microvilli height in Tff3-deficient females compared to that in Wt females, suggesting a possible effect on microvillar actin filament dynamics. These changes could not be attributed to genes involved in ER and oxidative stress, apoptosis, or inflammation. Tff3-deficient males exhibited a reduced cecal crypt depth compared to that of Wt males, but this was not the case in females. Microbiome-related short-chain fatty acid content was not affected by Tff3 deficiency in HFD-fed male or female mice. Sex-related differences due to Tff3 deficiency imply the need to consider both sexes in future studies on the role of Tff in intestinal function.

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Effect of Tff3 Deficiency and ER Stress in the Liver

Cited by 8 publications

References 69 publications

Intestinal activating transcription factor 4 regulates stress-related behavioral alterations via paraventricular thalamus in male mice

Intestinal activating transcription factor 4 regulates stress-related behavioral alterations via paraventricular thalamus in male mice

Pathological and therapeutic roles of bioactive peptide trefoil factor 3 in diverse diseases: recent progress and perspective

Tff3 Deficiency Differentially Affects the Morphology of Male and Female Intestines in a Long-Term High-Fat-Diet-Fed Mouse Model

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