Abstract
The liver plays a pivotal role in maintaining euglycemia. Biogenesis and function of mitochondria within hepatocytes are often the first to be damaged in a diabetic population, and restoring its function is recently believed to be a promising strategy on inhibiting the progression of diabetes. Previously, we demonstrated that the gut microbiota metabolite butyrate could reduce hyperglycemia and modulate the metabolism of glycogen in both db/db mice and HepG2 cells. To further explore the mechanism of butyrate in controlling energy metabolism, we investigated its influence and underlying mechanism on the biogenesis and function of mitochondria within high insulin-induced hepatocytes in this study. We found that butyrate significantly modulated the expression of 54 genes participating in mitochondrial energy metabolism by a PCR array kit, both the content of mitochondrial DNA and production of ATP were enhanced, expressions of histone deacetylases 3 and 4 were inhibited, beta-oxidation of fatty acids was increased, and oxidative stress damage was ameliorated at the same time. A mechanism study showed that expression of GPR43 and its downstream protein beta-arrestin2 was increased on butyrate administration and that activation of Akt was inhibited, while the AMPK-PGC-1alpha signaling pathway and expression of p-GSK3 were enhanced. In conclusion, we found in the present study that butyrate could significantly promote biogenesis and function of mitochondria under high insulin circumstances, and the GPR43-β-arrestin2-AMPK-PGC1-alpha signaling pathway contributed to these effects. Our present findings will bring new insight on the pivotal role of metabolites from microbiota on maintaining euglycemia in diabetic population.
Highlights
Type 2 diabetes (T2D) has become a major threat to health worldwide
We demonstrated in db/db mice that oral administration with sodium butyrate (NaB) significantly reduced HbA1c and diabetic inflammation [7]; more importantly, hypertrophy and steatosis of hepatocytes in db/db mice were significantly reversed by NaB, accompanied with enhancement of glycogen metabolism [8]
As mitochondria play a pivotal role in modulating energy balance, we further carried out experiments to investigate influence of NaB on mitochondria under insulin resistance (IR) circumstances
Summary
Type 2 diabetes (T2D) has become a major threat to health worldwide. It is estimated that the diabetic population will rise to 600 million people within the 20 years, accounting for about 10% of the world population. The liver plays a pivotal role in maintaining euglycemia; as high as 19% of cases with type 2 diabetes are reported being accompanied with liver dysfunction [1]. The liver is one of the main target organs for insulin. By modulating glycogenesis or glucose oxidation within hepatocytes, blood glucose is maintained in a relatively stable state. A very high level of insulin, or the so-called insulin resistance (IR), will significantly destroy the capacity of the Oxidative Medicine and Cellular Longevity
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