Oral administration of tributyrin increases concentration of butyrate in the portal vein and prevents lipopolysaccharide-induced liver injury in rats

Miyoshi, Makoto; Sakaki, Hiroe; Usami, Makoto; Iizuka, Norihito; Shuno, Katsuhito; Aoyama, Masayuki; Usami, Yu

doi:10.1016/j.clnu.2010.09.012

Cited by 75 publications

(54 citation statements)

References 29 publications

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“…Tb treatment also attenuated the hepatic steatosis induced by a high-fat diet. This protective effect of Tb has also been demonstrated in endotoxemic rats and seems to involve inhibition of NF-B (29).…”

Section: Discussionmentioning

confidence: 86%

“…The major problem of using this compound in vivo has been the difficulty in achieving and maintaining its concentrations in blood since this fatty acid is rapidly metabolized by colonocytes. To overcome this problem, we have used Tb, a prodrug of butyrate that presents low toxicity and has been shown to increase plasmatic butyrate levels up to 2.4 mM and to sustain butyrate concentrations above 0.1 mM for more than 120 min after oral administration (8,29).…”

Section: Discussionmentioning

confidence: 99%

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Tributyrin attenuates obesity-associated inflammation and insulin resistance in high-fat-fed mice

Vinolo

Rodrigues

Festuccia

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

135

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-The aim of this study was to investigate whether treatment with tributyrin (Tb; a butyrate prodrug) results in protection against diet-induced obesity and associated insulin resistance. C57BL/6 male mice fed a standard chow or high-fat diet were treated with Tb (2 g/kg body wt, 10 wk) and evaluated for glucose homeostasis, plasma lipid profile, and inflammatory status. Tb protected mice against obesity and obesityassociated insulin resistance and dyslipidemia without food consumption being affected. Tb attenuated the production of TNF␣ and IL-1␤ by peritoneal macrophages and their expression in adipose tissue. Furthermore, in the adipose tissue, Tb reduced the expression of MCP-1 and infiltration by leukocytes and restored the production of adiponectin. These effects were associated with a partial reversion of hepatic steatosis, reduction in liver and skeletal muscle content of phosphorylated JNK, and an improvement in muscle insulin-stimulated glucose uptake and Akt signaling. Although part of the beneficial effects of Tb are likely to be secondary to the reduction in body weight, we also found direct protective actions of butyrate reducing TNF␣ production after LPS injection and in vitro by LPS-or palmitic acid-stimulated macrophages and attenuating lipolysis in vitro and in vivo. The results, reported herein, suggest that Tb may be useful for the treatment and prevention of obesity-related metabolic disorders.butyrate; macrophages; diabetes; cytokines; white adipose tissue THE CHRONIC LOW-GRADE INFLAMMATION associated with obesity plays a central role as a link between excessive fat accumulation and the development of pathologies (20). In obesity, adipose tissue is markedly infiltrated by proinflammatory macrophages and other leukocytes that secrete proinflammatory cytokines and chemokines (20,41,50). The overproduction of these inflammatory mediators together with changes in adipokine production and nonesterified fatty acid (NEFA) levels leads to the development of insulin resistance. In addition to adipose tissue, several organs, including the liver (1) and hypothalamus (28), develop a proinflammatory profile in response to the excessive nutrient supply. This systemic inflammatory state is associated with the activation of intracellular signaling pathways such as JUN NH 2 -terminal kinase (JNK) and IB kinase-␤ (IKK␤) that in turn phosphorylate serine residues in the insulin receptor substrate, inhibiting tyrosine phosphorylation and the interaction with phosphatidylinositol-3 kinase (19,21).In accord with an important role of inflammation in the development of obesity-associated diseases, whole body deletion of intracellular kinases activated upon inflammation, namely JNK (18) and IKK␤ (1), and pharmacological treatment with anti-inflammatory agents such as -3 fatty acids and salsalate, a salicylate derivate, were demonstrated to protect mice from the deleterious effects of high-fat feeding and obesity on insulin sensitivity (16,32).Butyrate is a short-chain fatty acid (SCFA) produced during fermentation o...

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Tributyrin attenuates obesity-associated inflammation and insulin resistance in high-fat-fed mice

Vinolo

Rodrigues

Festuccia

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

135

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“…1C shows the downregulation of the immune response to LPS following butyrate administration. Butyrate has been well known as a Histone Deacetylase (HDAC) inhibitor and its effects in attenuating inflammatory Science Publications AJAVS conditions have been hypothesized to be the result of modulation of the NF-κB signalling cascade at multiple levels (Miyoshi et al, 2011). TLR4/NF-κB controls the expression of many inflammatory genes (Fig.…”

Section: Gene Expression and Pathway Analysismentioning

confidence: 99%

Butyrate-Mediated Genomic Changes Involved in Non-Specific Host Defenses, Matrix Remodeling and the Immune Response in the Rumen Epithelium of Cows Afflicted With Subacute Ruminal Acidosis

Dionissopoulos

Laarman

AlZahal

et al. 2013

American Journal of Animal and Veterinary Sciences

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Subacute Ruminal Acidosis (SARA) is a disorder in cattle which can lead to chronic inflammation in the rumen epithelium, known as rumenitis. Butyrate has been shown to attenuate some of the detrimental effects of inflammatory gastroenteral disorders but the molecular mechanisms mediated by butyrate have not been defined. The objective of this study was to define the inflammatory-related genomic changes responsible for the beneficial effects of butyrate. Experimentally, 16 fistulated dairy cows at mid-lactation were fed a SARA-inducing (45% non-fiber carbohydrate) diet beginning 2 days before the beginning of treatment and continuing throughout the experiment. Cows were then evenly divided into treatment groups where a carrier with (n = 8) or without (n = 8) supplemental butyrate (2.5% initial DM intake) was deposited into the rumen daily for 7 days. The minimum rumen pH was higher in cows with supplemental butyrate (4.96±0.09 to 5.20±0.05, p = 0.040), but mean pH, maximum pH and the duration for which rumen pH was below 5.6 was unaffected. Free plasma Lipopolysaccharide (LPS) concentration was unaffected by treatment as was the concentration of Serum Amyloid A (SAA), although the LPS Binding Protein (LBP) concentration was increased by the addition of butyrate to the rumen (6.91±0.29 to 7.93±0.29 µg mL −1 , p = 0.024). Of the rumen Short Chain Fatty Acids (SCFA) tested, only butyrate showed a pronounced treatment effect, rising from 8.60±0.94 to 21.60±0.94 mM (p≤0.0001). Plasma Beta-Hydroxybutyrate (BHBA) concentration also increased (799.50±265.24 to 3261.63±265.24 µM, p≤0.001). Butyrate infusion did not affect milk parameters (total fat, lactose, total protein and LOS); however, when related to dry matter intake, milk production efficiency was increased (p = 0.035). Microarray and qRT-PCR analyses of rumen papillae biopsies collected on day 7 found that butyrate administration affected (p≤0.05) the expression of genes involved in Non-Specific Host Defense (NSHD), Remodeling or adaptation (RM) and Immune Response (IR). Of the 49 genes tested by qRT-PCR, 9 (LCN2, MMP1, MUC16, GPX2, CSTA, FUT1, SERPINE2, BCAM, RAC3) were upregulated, 20 (MTOR, AKIRIN2, NFKBIZ, NFKB2, ACVR2A, LAMB1, FRS2, PPARD, LBP, NEDD4L, SGK1, DEDD2, MAP3K8, PARD6B, PLIN2, ADA, HPGD, FMO5, BMP6, TCHH) were downregulated and 20 were unchanged due to butyrate administration in the proximal gastrointestinal tract. AJAVSThese results demonstrate the potential protective effect and molecular mechanisms involved in a novel butyrate treatment for inflammatory gastrointestinal conditions.

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“…However, visceral fat is exposed to higher levels of SCFAs in the portal circulation, which can reach 0.45 mmol/ L 37) , although the composition of SCFAs in the portal vein is affected by diet to a greater extent than in the peripheral circulation. To overcome low butyrate levels in animal experiments, tributyrin, a prodrug of butyrate with low toxicity, has been used to increase plasma butyrate levels up to 2.4 mmol/L at 1 h, with levels maintained at 0.7 mmol/L in the portal vein of mice at 2.5 h after oral administration 17) . Thus, the effects…”

Section: Acknowledgementsmentioning

confidence: 99%

“…With respect to the underlying mechanism, butyrate is known to prevent the degradation of inhibitor kappaB-alpha (IκB-α) and to regulate the production of inflammatory mediators 15,16) . A recent study revealed that oral administration of tributyrin (a prodrug of butyrate) attenuated endotoxin-induced hepatic injury via downregulation of Toll-like receptor 2 (TLR2), TNF-α and nuclear factor-kappaB (NF-κB) 17) . Since SCFA receptors, such as G protein coupled receptor 41 or 43 (GPR41,43), are highly expressed in both adipocytes and macrophages 18,19) , butyrate may have synergistic effects on both cell types.…”

Section: Introductionmentioning

confidence: 99%

Butyrate Attenuates Inflammation and Lipolysis Generated by the Interaction of Adipocytes and Macrophages

Ohira

Fujioka

Katagiri

et al. 2013

JAT

Self Cite

174

131

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Aim: Paracrine interaction between macrophages and adipocytes in obese visceral fat tissues is thought to be a trigger of chronic inflammation. The immunomodulatory effect of the short chain fatty acid, butyric acid, has been demonstrated. We hypothesize that sodium butyrate (butyrate) attenuates inflammatory responses and lipolysis generated by the interaction of macrophages and adipocytes. Methods: Using contact or transwell co-culture methods with differentiated 3T3-L1 adipocytes and RAW264.7 macrophages, we investigated the effects of butyrate on the production of tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), and the release of free glycerol, free fatty acids (FFAs) into the medium. We also examined the activity of nuclear factor-kappaB (NF-κB) and the phosphorylation of mitogen-activated protein kinases (MAPKs) in co-cultured macrophages, as well as lipase activity and expression in co-cultured adipocytes. Results: We found increased production of TNF-α, MCP-1, IL-6, and free glycerol, FFAs in the coculture medium, and butyrate significantly reduced them. Butyrate inhibited the phosphorylation of MAPKs, the activity of NF-κB in co-cultured macrophages, and suppressed lipase activity in co-cultured adipocytes. Lipase inhibitors significantly attenuated the production of TNF-α, MCP-1 and IL-6 in the co-culture medium as effectively as butyrate. Butyrate suppressed the protein production of adipose triglyceride lipase, hormone sensitive lipase, and fatty acid-binding protein 4 in co-cultured adipocytes. Pertussis toxin, which is known to block GPR41 completely, inhibited the antilipolysis effect of butyrate. Conclusion: Butyrate suppresses inflammatory responses generated by the interaction of adipocytes and macrophages through reduced lipolysis and inhibition of inflammatory signaling.

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Oral administration of tributyrin increases concentration of butyrate in the portal vein and prevents lipopolysaccharide-induced liver injury in rats

Cited by 75 publications

References 29 publications

Tributyrin attenuates obesity-associated inflammation and insulin resistance in high-fat-fed mice

Tributyrin attenuates obesity-associated inflammation and insulin resistance in high-fat-fed mice

Butyrate-Mediated Genomic Changes Involved in Non-Specific Host Defenses, Matrix Remodeling and the Immune Response in the Rumen Epithelium of Cows Afflicted With Subacute Ruminal Acidosis

Butyrate Attenuates Inflammation and Lipolysis Generated by the Interaction of Adipocytes and Macrophages

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