Sodium Butyrate Ameliorates High-Fat-Diet-Induced Non-alcoholic Fatty Liver Disease through Peroxisome Proliferator-Activated Receptor α-Mediated Activation of β Oxidation and Suppression of Inflammation

Abstract

Peroxisome proliferator-activated receptor α (PPARα) plays a protective role against non-alcoholic fatty liver disease (NAFLD). Sodium butyrate (NaB) has been shown to alleviate NAFLD, yet whether and how PPARα is involved in the action of NaB remains elusive. In this study, NaB administration alleviated high-fat-diet-induced NAFLD in adult rats, with a decrease of hepatic triglyceride content from 108.18 ± 5.77 to 81.34 ± 7.94 μg/mg ( p < 0.05), which was associated with a significant activation of PPARα. Nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB)-mediated nucleotide-binding domain-like receptor protein 3 signaling and pro-inflammatory cytokine release were diminished by NaB treatment. NaB-induced PPARα upregulation coincided with a reduced protein content of histone deacetylase 1 and promoted histone H3 acetyl K9 (H3K9Ac) modification on the promoter of PPARα, whereas NaB-induced suppression of inflammation was linked to significantly increased PPARα binding with p-p65. NaB acts as a histone deacetylase inhibitor to upregulate PPARα expression with enhanced H3K9Ac modification on it promoter. NaB-induced PPARα activation stimulates fatty acid β oxidation and inhibits NF-κB-mediated inflammation pathways via protein-protein interaction, thus contributing to amelioration of high-fat-diet-induced NAFLD in adult rats.

The role of the microbiome in NAFLD and NASH

“…Zhou et al (2017a) reported that FMT attenuated high-fat diet-induced NASH in mice via beneficial regulation of gut microbiota. The administration of butyrate, a SCFA, effectively ameliorates lipid accumulation and liver inflammation in animal NAFLD models, through modulation of gut microbiota and gut barrier function (Zhou et al, 2017b), attenuation of inducible nitric oxide synthase (iNOS) induction (Jin et al, 2016), and suppression of inflammatory pathways (Sun et al, 2018). The effect of FMT on NAFLD/NASH is just beginning to be investigated and requires more animal and human clinical studies.…”

“…Pharmaceuticals targeting bile acid dysregulation in NAFLD, including FXR agonists, PPARa agonists, ursodeoxycholic acid (UDCA), and its derivatives, have entered different phases of clinical trials, and some of them have shown promising therapeutic effects (Yu et al, 2018). The administration of butyrate, a SCFA, effectively ameliorates lipid accumulation and liver inflammation in animal NAFLD models, through modulation of gut microbiota and gut barrier function (Zhou et al, 2017b), attenuation of inducible nitric oxide synthase (iNOS) induction (Jin et al, 2016), and suppression of inflammatory pathways (Sun et al, 2018).…”

Oral Supplementation of Sodium Butyrate Attenuates the Progression of Non-Alcoholic Steatohepatitis

“…Recently, oral butyrate supplementation was reported to decrease cytokine release in patients with metabolic syndrome [13]. In addition, studies also suggest that an oral supplementation of therapeutic doses of sodium butyrate (SoB) (0.2-0.6 g/kg bw/d) may attenuate insulin resistance and the development of NAFLD, e.g., steatosis, inflammation and even early signs of fibrosis in rodents [6,[14][15][16]. In these studies, it was shown that the beneficial effects of SoB on the development of NAFLD are associated with protection against the induction of inducible nitric oxide synthase (iNOS) and lipid peroxidation.…”

Gut microbiota and butyrate contribute to nonalcoholic fatty liver disease in premenopause due to estrogen deficiency

“…Increased uptake of circulating FA, increased hepatic lipogenesis, reduced rate of FA oxidation and reduced FA secretion are the multiple mechanisms that lead to an increased accumulation of lipids in the liver [36]. Studies have shown that butyrate restores PPARα activation in HFD fed rats, thus enhancing FA β-oxidation, inhibiting lipid synthesis and downregulating nuclear factor-kappa B pathways and inflammation [37][38]. In the current report, our data also showed that OVX mice with decreased butyrate content had upregulation of FA intake and synthesis but downregulation of oxidation related gene and protein expression.…”