scholarly journals Role of TNFR1 and TNFR2 receptors in tubulointerstitial fibrosis of obstructive nephropathy

1999 ◽  
Vol 277 (5) ◽  
pp. F766-F772 ◽  
Author(s):  
Guangjie Guo ◽  
Jeremiah Morrissey ◽  
Ruth McCracken ◽  
Timothy Tolley ◽  
Saulo Klahr
Keyword(s):  
Knockout Mice ◽  
Ureteral Obstruction ◽  
Collagen Iv ◽  
Tubulointerstitial Fibrosis ◽  
Kidney Cortex ◽  
Mrna Levels ◽  
Ang Ii ◽  
Wild Type ◽  
Interstitial Volume ◽  
Tnf Α

Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the obstructed kidney. In this study, we report the contribution of tumor necrosis factor-α (TNF-α) to the fibrosis that develops after ureteral obstruction. Mice in which individual TNF-α receptors TNFR1 or TNFR2 had been genetically knocked out were used, and results were compared with mice of C57Bl/6 background after 5 days UUO. Both kidneys were removed and examined histologically for changes in interstitial volume (Vvint), collagen IV deposition, α-smooth muscle actin (α-SMA) matrix score, nuclear factor-κB (NF-κB) activity, and TNF-α mRNA levels. We found that the Vvint of contralateral unobstructed kidneys averaged ∼7% and was indistinguishable among the three genotypes of mice. Vvintof ureteral obstructed kidney of C57Bl/6 mice averaged 33 ± 3.9% after 5 days of UUO. Vvint of obstructed kidneys of TNFR1 mice was significantly reduced to 19.4 ± 3.1%, whereas that of TNFR2 mice was significantly decreased to 25.4% ± 4.8%. There was a modest but significant difference between Vvint of TNFR1 and TNFR2 ( P < 0.047). Both collagen IV and α-SMA matrix scores were decreased significantly in obstructed kidney of TNFR1 mouse compared with that of C57Bl/6 and TNFR2 mice. Nuclear extracts prepared from kidney cortex were found to have a significant increase in NF-κB binding activity in obstructed kidney compared with contralateral kidney. Individual knockout of the TNFR1 or TNFR2 genes resulted in significantly less NF-κB activation compared with the wild type, with TNFR1 being less than TNFR2 knockout. There was a significant increase in TNF-α mRNA in the kidney with ureteral obstruction in all three genotypes. TNFR1 knockout displayed a significant reduction in amount of TNF-α mRNA induced compared with wild-type or TNFR2 knockout mice. Treatment of TNFR1 knockout mice with an angiotensin converting enzyme inhibitor further decreased Vvint and TNF-α mRNA induction, suggesting an interaction of ANG II and TNF-α systems. These results suggest that TNF-α contributes, in part, to changes in interstitial volume, myofibroblast differentiation, and NF-κB activation in the kidney during ureteral obstruction. These changes appear to be mediated through both TNFR1 and TNFR2 gene products with effects through the TNFR1 receptor predominating. Furthermore, ANG II appears to stimulate TNF-α pathophysiological events leading to renal fibrosis.

Sepsis in mice stimulates muscle proteolysis in the absence of IL-6

1998 ◽  
Vol 275 (6) ◽  
pp. R1983-R1991 ◽  
Author(s):  
Arthur Williams ◽  
Jing Jing Wang ◽  
Li Wang ◽  
Xiaoyan Sun ◽  
Josef E. Fischer ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Muscle Protein ◽  
Mrna Levels ◽  
Protein Breakdown ◽  
Wild Type ◽  
Dot Blot ◽  
Muscle Protein Breakdown ◽  
L6 Myotubes ◽  
Identical Response ◽  
Breakdown Rates

We tested the role of interleukin-6 (IL-6) in sepsis-induced muscle proteolysis by determining ubiquitin mRNA levels and protein breakdown rates in incubated extensor digitorum longus muscles from septic and sham-operated IL-6 knockout and wild-type mice. In addition, the effect of treatment of mice with human recombinant IL-6 on muscle protein breakdown rates was determined. Finally, protein breakdown rates were measured in myotubes treated for up to 48 h with different concentrations of IL-6. Sepsis in wild-type mice resulted in an approximately ninefold increase in plasma IL-6 levels, whereas IL-6 was not detectable in plasma of sham-operated or septic IL-6 knockout mice. Total and myofibrillar muscle protein breakdown rates were increased by ∼30% and threefold, respectively, in septic IL-6 wild-type mice with an almost identical response noted in septic IL-6 knockout mice. Ubiquitin mRNA levels determined by dot blot analysis were increased during sepsis in muscles from both IL-6 knockout and wild-type mice, although the increase was less pronounced in IL-6 knockout than in wild-type mice. Treatment of normal mice or of cultured L6 myotubes with IL-6 did not influence protein breakdown rates. The present results suggest that IL-6 does not regulate muscle proteolysis during sepsis.

Changes in angiotensin type 1 receptor binding and angiotensin-induced pressor responses in the rostral ventrolateral medulla of angiotensinogen knockout mice

2010 ◽  
Vol 298 (2) ◽  
pp. R411-R418 ◽  
Author(s):  
Daian Chen ◽  
Lisa Hazelwood ◽  
Lesley L. Walker ◽  
Brian J. Oldfield ◽  
Michael J. McKinley ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Receptor Binding ◽  
Knockout Mice ◽  
Pressor Response ◽  
Ventrolateral Medulla ◽  
Ang Ii ◽  
Wild Type ◽  
Intravenous Injections ◽  
Angiotensin Type

ANG II, the main circulating effector hormone of the renin-angiotensin system, is produced by enzymatic cleavage of angiotensinogen. The present study aimed to examine whether targeted deletion of the angiotensinogen gene ( Agt) altered brain ANG II receptor density or responsiveness to ANG II. In vitro autoradiography was used to examine the distribution and density of angiotensin type 1 (AT1) and type 2 receptors. In most brain regions, the distribution and density of angiotensin receptors were similar in brains of Agt knockout mice ( Agt −/− ) and wild-type mice. In Agt −/− mice, a small increase in AT1 receptor binding was observed in the rostral ventrolateral medulla (RVLM), a region that plays a critical role in blood pressure regulation. To examine whether Agt −/− mice showed altered responses to ANG II, blood pressure responses to intravenous injection (0.01–0.1 μg/kg) or RVLM microinjection (50 pmol in 50 nl) of ANG II were recorded in anesthetized Agt −/− and wild-type mice. Intravenous injections of phenylephrine (4 μg/kg and 2 μg/kg) were also made in both groups. The magnitude of the pressor response to intravenous injections of ANG II or phenylephrine was not different between Agt −/− and wild-type mice. Microinjection of ANG II into the RVLM induced a pressor response, which was significantly smaller in Agt −/− compared with wild-type mice (+10 ± 1 vs. +23 ± 4 mmHg, respectively, P = 0.004). Microinjection of glutamate into the RVLM (100 pmol in 10 nl) produced a robust pressor response, which was not different between Agt −/− and wild-type mice. A diminished response to ANG II microinjection in the RVLM of Agt −/− mice, despite an increased density of AT1 receptors suggests that signal transduction pathways may be altered in RVLM neurons of Agt −/− mice, resulting in attenuated cellular excitation.

scholarly journals The effect of long-term dehydration and subsequent rehydration on markers of inflammation, oxidative stress and apoptosis in the camel kidney

2020 ◽  
Vol 16 (1) ◽  
Author(s):  
Mahmoud A. Ali ◽  
Hassan Abu Damir ◽  
Osman M. Ali ◽  
Naheed Amir ◽  
Saeed Tariq ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Water Conservation ◽  
Mesangial Cells ◽  
Expression Level ◽  
Kidney Cortex ◽  
Mrna Levels ◽  
Sod Activity ◽  
Markers Of Inflammation ◽  
Tnf Α ◽  
Different Response

Abstract Background Dehydration has deleterious effects in many species, but camels tolerate long periods of water deprivation without serious health compromise. The kidney plays crucial role in water conservation, however, some reports point to elevated kidney function tests in dehydrated camels. In this work, we investigated the effects of dehydration and rehydration on kidney cortex and medulla with respect to pro-inflammatory markers, oxidative stress and apoptosis along with corresponding gene expression. Results The cytokines IL-1β and IL-18 levels were significantly elevated in the kidney cortex of dehydrated camel, possibly expressed by tubular epithelium, podocytes and/or mesangial cells. Elevation of IL-18 persisted after rehydration. Dehydration induced oxidative stress in kidney cortex evident by significant increases in MDA and GSH, but significant decreases in SOD and CAT. In the medulla, CAT decreased significantly, but MDA, GSH and SOD levels were not affected. Rehydration abolished the oxidative stress. In parallel with the increased levels of MDA, we observed increased levels of PTGS1 mRNA, in MDA synthesis pathway. GCLC mRNA expression level, involved in GSH synthesis, was upregulated in kidney cortex by rehydration. However, both SOD1 and SOD3 mRNA levels dropped, in parallel with SOD activity, in the cortex by dehydration. There were significant increases in caspases 3 and 9, p53 and PARP1, indicating apoptosis was triggered by intrinsic pathway. Expression of BCL2l1 mRNA levels, encoding for BCL-xL, was down regulated by dehydration in cortex. CASP3 expression level increased significantly in medulla by dehydration and continued after rehydration whereas TP53 expression increased in cortex by rehydration. Changes in caspase 8 and TNF-α were negligible to instigate extrinsic apoptotic trail. Generally, apoptotic markers were extremely variable after rehydration indicating that animals did not fully recover within three days. Conclusions Dehydration causes oxidative stress in kidney cortex and apoptosis in cortex and medulla. Kidney cortex and medulla were not homogeneous in all parameters investigated indicating different response to dehydration/rehydration. Some changes in tested parameters directly correlate with alteration in steady-state mRNA levels.

scholarly journals Pregnant rats treated with a high-fat/prooxidant Western diet with ANG II and TNF-α are resistant to elevations in blood pressure and renal oxidative stress

2015 ◽  
Vol 308 (11) ◽  
pp. R945-R956 ◽  
Author(s):  
Mark W. Cunningham ◽  
Crystal A. West ◽  
Xuerong Wen ◽  
Aihua Deng ◽  
Chris Baylis
Keyword(s):  
Oxidative Stress ◽  
Western Diet ◽  
Kidney Cortex ◽  
Ang Ii ◽  
Sprague Dawley ◽  
High Fat ◽  
Redox Systems ◽  
Plasma Protein Concentration ◽  
Pregnant Rats ◽  
Tnf Α

Oxidative stress and inflammation are risk factors for hypertension in pregnancy. Here, we examined the 24-h mean arterial pressure (MAP) via telemetry and the nitric oxide (NO) and redox systems in the kidney cortex, medulla, and aorta of virgin and pregnant rats treated with a high-fat/prooxidant Western diet (HFD), ANG II, and TNF-α. Female Sprague-Dawley rats were given a normal diet (ND) or a HFD for 8 wk before mating. Day 6 of pregnancy and age-matched virgins were implanted with minipumps infusing saline or ANG II (150 ng·kg−1·min−1) + TNF-α (75 ng/day) for 14 days. Groups consisted of Virgin + ND + Saline (V+ND) ( n = 7), Virgin + HFD +ANG II and TNF-α (V+HFD) ( n = 7), Pregnant + ND + Saline (P+ND) ( n = 6), and Pregnant + HFD + ANG II and TNF-α (P+HFD) ( n = 8). After day 6 of minipump implantation, V+HFD rats displayed an increase in MAP on days 7, 8, and 10–15 vs. V+ND rats. P+HFD rats, after day 6 of minipump implantation, showed an increase in MAP only on day 7 vs. P+ND rats. P+HFD rats had a normal fall in 24-h MAP, hematocrit, plasma protein concentration, and osmolality at late pregnancy. No change in kidney cortex, medulla, or aortic oxidative stress in P+HFD rats. P+HFD rats displayed a decrease in nNOSβ abundance, but no change in kidney cortex NOxcontent vs. P+ND rats. Pregnant rats subjected to a chronic HFD and prooxidant and proinflammatory insults have a blunted increase in 24-h MAP and renal oxidative stress. Our data suggest renal NO bioavailability is not altered in pregnant rats treated with a HFD, ANG II, and TNF-α.

Role of α2-macroglobulin in fever and cytokine responses induced by lipopolysaccharide in mice

2002 ◽  
Vol 283 (1) ◽  
pp. R218-R226 ◽  
Author(s):  
Alexander V. Gourine ◽  
Valery N. Gourine ◽  
Yohannes Tesfaigzi ◽  
Nathalie Caluwaerts ◽  
Fred Van Leuven ◽  
...  
Keyword(s):  
Mrna Level ◽  
Physiological Role ◽  
Mrna Levels ◽  
Wild Type ◽  
Cytokine Responses ◽  
Α2 Macroglobulin ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

α2-Macroglobulin (α2M) is not only a proteinase inhibitor in mammals, but it is also a specific cytokine carrier that binds pro- and anti-inflammatory cytokines implicated in fever, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). To define the role of α2M in regulation of febrile and cytokine responses, wild-type mice and mice deficient in α2M (α2M −/−) were injected with lipopolysaccharide (LPS). Changes in body temperature as well as plasma levels of IL-1β, IL-6, and TNF-α and hepatic TNF-α mRNA level during fever in α2M −/− mice were compared with those in wild-type control mice. The α2M −/− mice developed a short-term markedly attenuated (ANOVA, P < 0.05) fever in response to LPS (2.5 mg/kg ip) compared with the wild-type mice. At 1.5 h after injection of LPS, the plasma concentration of TNF-α, but not IL-1β or IL-6, was significantly lower (by 58%) in the α2M −/− mice compared with their wild-type controls (ANOVA, P < 0.05). There was no difference in hepatic TNF-α mRNA levels between α2M −/− and wild-type mice 1.5 h after injection of LPS. These data support the hypotheses that 1) α2M is important for the normal development of LPS-induced fever and 2) a putative mechanism of α2M involvement in fever is through the inhibition of TNF-α clearance. These findings indicate a novel physiological role for α2M.

Activation of the MyD88 signaling pathway inhibits ischemia-reperfusion injury in the small intestine

2012 ◽  
Vol 303 (3) ◽  
pp. G324-G334 ◽  
Author(s):  
Toshio Watanabe ◽  
Atsushi Kobata ◽  
Tetsuya Tanigawa ◽  
Yuji Nadatani ◽  
Hirokazu Yamagami ◽  
...  
Keyword(s):  
Small Intestine ◽  
Signaling Pathway ◽  
Knockout Mice ◽  
Ischemia Reperfusion ◽  
Adaptor Protein ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Tnf Α ◽  
Cox 2 ◽  
Myd88 Signaling

Toll-like receptors (TLRs) recognize microbial components and trigger the signaling cascade that activates innate and adaptive immunity. Recent studies have shown that the activation of TLR-dependent signaling pathways plays important roles in the pathogenesis of ischemia-reperfusion (I/R) injuries in many organs. All TLRs, except TLR3, use a common adaptor protein, MyD88, to transduce activation signals. We investigated the role of MyD88 in I/R injury of the small intestine. MyD88 and cyclooxygenase-2 (COX-2) knockout and wild-type mice were subjected to intestinal I/R injury. I/R-induced small intestinal injury was characterized by infiltration of inflammatory cells, disruption of the mucosal epithelium, destruction of villi, and increases in myeloperoxidase activity and mRNA levels of TNF-α and the IL-8 homolog KC. MyD88 deficiency worsened the severity of I/R injury, as assessed using the histological grading system, measuring luminal contents of hemoglobin (a marker of intestinal bleeding), and counting apoptotic epithelial cells, while it inhibited the increase in mRNA expression of TNF-α and KC. I/R significantly enhanced COX-2 expression and increased PGE2 concentration in the small intestine of wild-type mice, which were markedly inhibited by MyD88 deficiency. COX-2 knockout mice were also highly susceptible to intestinal I/R injury. Exogenous PGE2 reduced the severity of injury in both MyD88 and COX-2 knockout mice to the level of wild-type mice. These findings suggest that the MyD88 signaling pathway may inhibit I/R injury in the small intestine by inducing COX-2 expression.

scholarly journals Proximal tubule PPARα attenuates renal fibrosis and inflammation caused by unilateral ureteral obstruction

2013 ◽  
Vol 305 (5) ◽  
pp. F618-F627 ◽  
Author(s):  
Shenyang Li ◽  
Nithya Mariappan ◽  
Judit Megyesi ◽  
Brian Shank ◽  
Krishnaswamy Kannan ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Obstructive Uropathy ◽  
Kidney Tissue ◽  
Unilateral Ureteral Obstruction ◽  
Tubulointerstitial Fibrosis ◽  
Wild Type ◽  
Arginase 1

We examined the effects of increased expression of proximal tubule peroxisome proliferator-activated receptor (PPAR)α in a mouse model of renal fibrosis. After 5 days of unilateral ureteral obstruction (UUO), PPARα expression was significantly reduced in kidney tissue of wild-type mice but this downregulation was attenuated in proximal tubules of PPARα transgenic (Tg) mice. When compared with wild-type mice subjected to UUO, PPARα Tg mice had reduced mRNA and protein expression of proximal tubule transforming growth factor (TGF)-β1, with reduced production of extracellular matrix proteins including collagen 1, fibronectin, α-smooth muscle actin, and reduced tubulointerstitial fibrosis. UUO-mediated increased expression of microRNA 21 in kidney tissue was also reduced in PPARα Tg mice. Overexpression of PPARα in cultured proximal tubular cells by adenoviral transduction reduced aristolochic acid-mediated increased production of TGF-β, demonstrating PPARα signaling reduces epithelial TGF-β production. Flow cytometry studies of dissociated whole kidneys demonstrated reduced macrophage infiltration to kidney tissue in PPARα Tg mice after UUO. Increased expression of proinflammatory cytokines including IL-1β, IL-6, and TNF-α in wild-type mice was also significantly reduced in kidney tissue of PPARα Tg mice. In contrast, the expression of anti-inflammatory cytokines IL-10 and arginase-1 was significantly increased in kidney tissue of PPARα Tg mice when compared with wild-type mice subjected to UUO. Our studies demonstrate several mechanisms by which preserved expression of proximal tubule PPARα reduces tubulointerstitial fibrosis and inflammation associated with obstructive uropathy.

scholarly journals Dysregulated Macrophage Pro-Inflammatory Cytokine Production and Chronic Colitis in Mice Lacking Both Gab2 and Gab3

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 457-457
Author(s):  
Tamisha Y. Vaughan-Whitley ◽  
Hikaru Nishio ◽  
Barry Imhoff ◽  
Zhengqi Wang ◽  
Silvia T. Bunting ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Protein Expression ◽  
Knockout Mice ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Wild Type ◽  
Inflammatory Cytokine Production ◽  
Tnf Α ◽  
Single Knockout

Abstract Macrophages are responsible for protecting the body against foreign invaders. We have been studying the role of Grb2-associated binding proteins (Gabs) in macrophage biology. In mice, Gabs are adaptor proteins that include three family members (Gab1, Gab2, and Gab3) that play critical regulatory roles in modulating cytokine receptor signaling. Gab2 knockout mice have no developmental defects but have impaired allergic responses, osteoclast defects, altered mast cell development, and altered hematopoiesis. Gab3 knockout mice have no defined phenotypes alone and although highly expressed in macrophages, a functional role was not found despite considerable focus on this cell type. Therefore, we set out to determine the combined role of Gab2 and Gab3 to determine whether they performed redundant functions not observable in single knockout mice. To analyze regulation of macrophage cytokine production, a Gab2/3 deficient mouse model was generated on the C57BL/6 background. Bone Marrow Derived Macrophages (BMDM) were expanded from the bone marrow (BM) of wild-type (WT), Gab2 and Gab3 single knockout and Gab2/3 knockout mice and found to similarly co-express CD11b and F4/80. However, Gab2/3 knockout BM produced only 30% of wild-type BMDM numbers. Despite reductions in BMDM absolute numbers, isolated BMDM demonstrated significant induction of pro-inflammatory cytokines TNF-α and IL-12 and anti-inflammatory cytokine IL-10 mRNA at baseline. Interestingly, after LPS stimulation (100ng/ml) we detected much greater induction of TNF-α and IL-12 mRNA and protein expression. Interestingly, despite increased IL-10 mRNA induction in Gab2/3 knockout BMDM, no IL-10 protein expression could be detected by Luminex assay. No changes were observed in production of interferon or STAT1 activation in these BMDM. Studies have shown that rapamycin treatment of macrophages suppresses mTORC1 and subsequently reduces IL-10 production and promotes pro-inflammatory cytokine production. Gab2 is known for its role in regulating the PI3K pathway through interactions with the p85 regulatory subunit of PI3K. Therefore, we also examined whether mTOR activation was effected by Gab2/3 deficiency causing altered cytokine expression. Deletion of Gab2/3 in BMDMs treated with LPS showed an inhibition of 4EBP1 phosphorylation and increased AKT phosphorylation. These results suggest that Gabs may play a critical role in modulating mTOR activation and potentially causing defects in protein translation that reflect in reduced IL-10 cytokine levels in Gab2/3 knockout cells. IL-10 has a critical immunoregulatory role that is dysregulated in patients with inflammatory bowel disease. IL-10 deficient mice develop colitis due to loss of mucosal immune tolerance. Strikingly, as early as two months of age in vivo 12/32 (37.5%) Gab2/3 knockout mice developed rectal prolapse and suffered from diarrhea within a six month period. Histological analysis of isolated colons using a scoring system confirmed spontaneous development of colitis in Gab2/3 knockout mice compared to no phenotypes observed in WT and single knockout controls. To determine whether the BM was directly involved in the disease, BM chimeras were generated using irradiated WT mice as recipients and Gab2/3 knockout mice as donors. Susceptible recipients receiving Gab2/3 knockout BM showed a more invasive colitis phenotype than the spontaneous disease and resulted in forced euthanization due to body weight decreases greater than 25%. Multiple ulcerations were present in most of the colon proximal region, with extensive epithelial damage, transmural inflammation, and in some mice adenocarcinoma. Notably, we did not observe adenocarcinoma in untransplanted Gab2/3 knockout mice, suggesting that epithelial deletion of Gab2/3 may suppress cancer whereas in the bone marrow chimera model, the epithelial cells are WT and can be transformed. Similar phenotypes were also observed in secondary transplant recipients. Lastly, treatment of Gab2/3 knockout mice with dextran-sodium-sulfate (DSS) induced rapid severe colitis that resulted in death of 80% and 40% of Gab2/3 knockout and WT mice respectively. Overall, these observations demonstrate a major redundant role for Gab2 and Gab3 in macrophage immune surveillance required for the prevention of colitis in mice. Disclosures No relevant conflicts of interest to declare.

scholarly journals ChREBP-Knockout Mice Show Sucrose Intolerance and Fructose Malabsorption

2018 ◽  
Author(s):  
Takehiro Kato ◽  
Katsumi Iizuka ◽  
Ken Takao ◽  
Yukio Horikawa ◽  
Tadahiro Kitamura ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Knockout Mice ◽  
Gene Deletion ◽  
Body Weight Loss ◽  
Mrna Levels ◽  
Wild Type ◽  
Glucose Levels ◽  
Fructose Malabsorption ◽  
Sucrose Diet ◽  
Alpha Glucosidase

We have previously reported that 60% sucrose diet-fed ChREBP knockout mice (KO) showed body weight loss resulting in lethality. We aimed to elucidate whether sucrose and fructose metabolism are impaired in KO. Wild type mice (WT) and KO were fed a diet containing 30% sucrose with/without 0.08% miglitol, an &alpha;-glucosidase inhibitor, and these effects on phenotypes were tested. Furthermore, we compared metabolic changes of oral and peritoneal fructose injection. Thirty percent sucrose diet feeding did not affect phenotypes in KO. However, miglitol induced lethality in 30% sucrose-fed KO. Thirty percent sucrose plus miglitol diet-fed KO showed increased cecal contents, increased fecal lactate contents, increased growth of lactobacillales and Bifidobacterium and decreased growth of clostridium cluster XIVa. ChREBP gene deletion suppressed the mRNA levels of sucrose and fructose related genes. Next, oral fructose injection did not affect plasma glucose levels and liver fructose contents; however, intestinal sucrose and fructose related mRNA levels were increased only in WT. In contrast, peritoneal fructose injection increased plasma glucose levels in both mice; however, the hepatic fructose content in KO was much higher owing to decreased hepatic Khk mRNA expression. Taken together, KO showed sucrose intolerance and fructose malabsorption owing to decreased gene expression.

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