Targeting gut microbiota-derived butyrate improves hepatic gluconeogenesis through the cAMP-PKA-GCN5 pathway in late pregnant sows.

Short chain fatty acids (SCFAs) produced by gut microbiota affected hepatic glucose metabolism via the gut-liver axis. The present study aimed to investigate the effects of butyrate produced by gut microbiota on hepatic gluconeogenesis in late-pregnancy sows. A total of 240 primiparous sows in late pregnancy were tested for blood glucose using a glucose meter before feeding and grouped according to their blood glucose level as follows: 0-3.0 mmol L-1 (low blood glucose group, LG group) and 3.1-5.0 mmol L-1 (normal blood glucose group, NG group). Colonic SCFAs and microbiota, SCFAs in the portal vein and liver, and acetylation and phosphorylation levels in the liver samples were analyzed. Hepatocytes from pregnant sows were examined for the effect of butyrate on hepatic glucose gluconeogenesis. In vivo experiments showed that the reproductive performance, serum glucose metabolism index, colonic butyrate and butyrate-producing bacteria decreased in the LG group compared with the NG group. Correlation analysis found a positive correlation among colonic butyrate, butyrate-producing bacteria and the serum glucose metabolism index. Moreover, the hepatic cAMP concentration, PKA activity, GCN5 phosphorylation, and the expression of G6P and PEPCK were decreased and PGC1-α acetylation was increased in the LG group compared with the NG group. In vitro, sodium butyrate significantly stimulated the cAMP concentration, PKA activity, GCN5 phosphorylation, and the expression of G6P and PEPCK and inhibited PGC-1α acetylation in the LG group of hepatocytes from late-pregnancy sows. Interestingly, another in vivo experiment showed that dietary 1-kestose, a natural regulator of gut bacteria, significantly increased butyrate and butyrate-producing bacteria, and improved the reproductive performance and serum glucose metabolism index in late-pregnancy sows. Taken together, we found that targeting gut microbiota-derived butyrate could improve hepatic gluconeogenesis through the cAMP-PKA-GCN5 pathway in late-pregnancy sows.

Acetylation of lactate dehydrogenase B drives NAFLD progression by impairing lactate clearance.

BACKGROUND & AIMS: Lactate has recently been reported to accumulate in the livers of patients progressing from simple steatosis to non-alcoholic steatohepatitis (NASH). However, the underlying mechanism(s) of lactate accumulation and the role of lactate in the progression of non-alcoholic fatty liver disease (NAFLD) are essentially unknown. METHODS: We compared the acetylome in liver samples taken from healthy individuals, patients with simple steatosis and patients with NASH to identify potential targets of acetylation with a role in lactate metabolism. Interactions between the acetylated target and acetyltransferases were measured in multiple cell lines. An acetyltransferase inhibitor was injected into high-fat diet (HFD)-fed mice to determine the role of lactate on NAFLD progression in vivo. RESULTS: Hyperacetylation of lactate dehydrogenase B (LDHB) was found to be associated with lactate accumulation in NAFL and NASH livers in humans and mice. P300/CBP-associated factor (PCAF)-mediated acetylation of LDHB K82 was found to significantly decrease LDHB activity and impair hepatic lactate clearance, resulting in lactate accumulation. Acetylated LDHB induced lactate accumulation which exacerbated lipid deposition and inflammatory responses by activating histone hyperacetylation in HFD-induced NASH. The administration of embelin, a PCAF inhibitor, and the generation of an acetylation-deficient mutant of LDHB ameliorated NASH. CONCLUSION: PCAF-dependent LDHB acetylation plays a key role in hepatic lipid accumulation and inflammatory responses by impairing lactate clearance; this process might be a potential therapeutic target for the treatment of NASH. LAY SUMMARY: Lactate is known to accumulate in the livers of patients during the progression of non-alcoholic fatty liver disease (NAFLD); however, the underlying mechanism(s) of this accumulation and its importance in disease progression are unknown. Herein, we show that the acetylation of an enzyme involved in lactate metabolism leads to impaired lactate clearance and exacerbates NAFLD progression.

Effects of dietary supplementation with yeast glycoprotein on growth performance, intestinal mucosal morphology, immune response and colonic microbiota in weaned piglets.

Antibiotics are commonly provided to weaned piglets; however, this practice has become controversial due to the increased occurrences of microbial resistance, and alternatives are needed. This study aimed to investigate the effects of dietary supplementation with yeast glycoprotein (YG) on growth performance, intestinal mucosal morphology, immune response and colonic microbiota in weaned piglets. A total of 240 weaned piglets (d 23 ± 2) from 16 pens (15 piglets per pen) were randomly allocated to an antibiotics group (25% quinocetone 200 mg kg-1 and 4% enduracidin 800 mg kg-1 of the basal diet) or a YG group (800 mg kg-1 YG of the basal diet), respectively. The trial lasted 14 days, and at the end of the trial, one piglet per pen was chosen to collect plasma, intestinal tissue and colonic digesta samples. The results indicate that piglets fed diets containing YG tended to show increased final body weight (0.05 < P < 0.1), increased average daily gain (P < 0.05) and decreased F/G (P < 0.05) when compared with the antibiotics group. Moreover, intestinal permeability showed that YG led to an improvement in the intestinal development via decreasing serum content of DAO (P < 0.01). Histological evaluations showed that YG contributed to the improvement of the intestinal development via increasing villous height (P < 0.05) and the villous height to crypt depth ratio (P < 0.01), and decreasing crypt depth (P < 0.01) and villous width (P < 0.05) in the ileum. Intestinal integrity also showed that YG was conducive to improvement of the intestinal development via upregulating the m-RNA expression of occludin (P < 0.05) in the duodenal and jejunal mucosa. Interestingly, YG supplementation downregulated the m-RNA expression of IL-12 (P < 0.05), upregulated the m-RNA expression of Hsp-70 (P < 0.05) in the duodenal mucosa, downregulated the m-RNA expression of Hsp-70 (P < 0.05) and IFN-γ (P < 0.05), upregulated the m-RNA expression of Hsp-90 (P < 0.05) in the jejunal mucosa, and upregulated the m-RNA expression of Hsp-70 (P < 0.05) in the ileal mucosa. On the other hand, colonic microbiota results showed that YG supplementation increased the relative abundance of Lactobacillus (P < 0.05) in the genus level. Colonic metabolite results showed that YG supplementation decreased the content of acetate (P < 0.05). Taken together, it is speculated that YG would be a potent alternative to prophylactic antibiotics in improving the gut health in weaned piglets.