Effects of Sodium Butyrate and Its Synthetic Amide Derivative on Liver Inflammation and Glucose Tolerance in an Animal Model of Steatosis Induced by High Fat Diet

Abstract

Background & AimsNonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. Insulin resistance (IR) appears to be critical in its pathogenesis. We evaluated the effects of sodium butyrate (butyrate) and its synthetic derivative N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA) in a rat model of insulin resistance and steatosis induced by high-fat diet (HFD).MethodsAfter weaning, young male Sprague-Dawley rats were divided into 4 groups receiving different diets for 6 weeks: 1. control group (standard diet); 2. HFD; 3. HFD plus butyrate (20 mg/kg/die) and 4. HFD plus FBA (42.5 mg/Kg/die, the equimolecular dose of butyrate). Liver tissues of the rats were analyzed by Western blot and real-time PCR. Insulin resistance, liver inflammation and Toll-like pattern modifications were determined.ResultsEvaluation of these two preparations of butyrate showed a reduction of liver steatosis and inflammation in HFD fed animals. The compounds showed a similar potency in the normalisation of several variables, such as transaminases, homeostasis model assessment for insulin resistance index, and glucose tolerance. Both treatments significantly reduced hepatic TNF-α expression and restored GLUTs and PPARs, either in liver or adipose tissue. Finally, FBA showed a higher potency in reducing pro-inflammatory parameters in the liver, via suppression of Toll-like receptors and NF-κB activation.ConclusionsOur results demonstrated a protective effect of butyrate in limiting molecular events underlying the onset of IR and NAFLD, suggesting a potential clinical relevance for this substance. In particular, its derivative, FBA, could represent an alternative therapeutic option to sodium butyrate, sharing a comparable efficacy, but a better palatability and compliance.

Sodium butyrate and its synthetic amide derivative modulate nociceptive behaviors in mice

“…SCFAs such as acetate, propionate and butyrate, derive from fermentation of undigested and unabsorbed carbohydrates by microflora and they are utilized by the colonic mucosa, contributing to host health and gut microbiota composition [22][23][24]. Butyrate does not only represent a local source of energy for colonocytes, but it also plays a role in the regulation of systemic functions, such as inflammation and pain perception [3,17,19,25].…”

“…Despite PPARs are mainly considered lipid sensors, regulating glucose and lipid metabolism in different tissues, their involvement in other physio-pathological conditions has been widely demonstrated [19,32,33]. Zapolska-Downar et al [28] reported a role for NF-kB and PPAR-␣ in the anti-inflammatory effects of butyrate in endothelial cells, as well as in colonocytes.…”

“…Zapolska-Downar et al [28] reported a role for NF-kB and PPAR-␣ in the anti-inflammatory effects of butyrate in endothelial cells, as well as in colonocytes. Moreover, many studies showed that this anti-inflammatory activity is also due to the up-regulation of PPAR-␥ [19,29,30]. Recently, Alex et al showed that butyrate induces the colonic expression and secretion of angiopoietin-like protein 4 (ANGPTL4), a circulating mediator which regulates gut microbiota, fat storage and inflammation, by activating PPAR-␥ [8].…”

“…Furthermore, we investigated whether the analgesic properties of butyrate can be achieved using the N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA), a more palatable butyrate-releasing compound [19].…”

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…However, as insulin resistance is associated with NAFLD, one could propose that butyrate may improve NAFLD. Indeed, Mattace Raso and coworkers showed that sodium butyrate protected high-fat fed rats from NAFLD (Mattace Raso et al, 2013). Altogether, these studies reveal a potentially important role of gut microbiota in the development of MetS, NAFLD and insulin resistance.…”