Role of serum- and glucocorticoid-inducible kinase 1 in the regulation of hepatic gluconeogenesis.

Excessive hepatic gluconeogenesis partially accounts for the occurrence of type 2 diabetes mellitus. Serum- and glucocorticoid inducible-kinase 1 (SGK1) is linked to the development of metabolic syndrome, such as obesity, hypertension, and hyperglycemia. However, the regulatory role of SGK1 in glucose metabolism of liver remains uncertain. Our microarray analysis showed that SGK1 expression was strongly induced by 8-Br-cAMP and suppressed by metformin in primary mouse hepatocytes. Hepatic SGK1 expression was markedly increased in obese and diabetic mice. Metformin treatment decreased hepatic SGK1 expression levels in db/db mice. Inhibition or knockdown of SGK1 suppressed gluconeogenesis in primary mouse hepatocytes, with decreased expressions of key gluconeogenic genes. Furthermore, SGK1 silencing in liver decreased hepatic glucose production in C57BL/6 mice. Knockdown of SGK1 had no impact on CREB phosphorylation level but increased AKT and FoxO1 phosphorylation levels with decreased expressions of transcription factors including FoxO1 and hepatocyte nuclear factors. Adenovirus-mediated expression of dominant-negative AMPK antagonized metformin-suppressed SGK1 expression induced by 8-Br-cAMP. These findings demonstrate that hepatic specific silence of SGK1 might be a potential therapeutic strategy for type 2 diabetes.

Sodium butyrate potentiates insulin secretion from rat islets at the expense of compromised expression of ß cell identity genes.

Short-chain fatty acids (SCFAs) produced by the gut microbiota have been well demonstrated to improve metabolic homeostasis. However, the role of SCFAs in islet function remains controversial. In the present study, none of the sodium acetate, sodium propionate, and sodium butyrate (SB) displayed acute impacts on insulin secretion from rat islets, whereas long-term incubation of the three SCFAs significantly potentiated pancreatic ß cell function. RNA sequencing (RNA-seq) revealed an unusual transcriptome change in SB-treated rat islets, with the downregulation of insulin secretion pathway and ß cell identity genes, including Pdx1, MafA, NeuroD1, Gck, and Slc2a2. But these ß cell identity genes were not governed by the pan-HDAC inhibitor trichostatin A. Overlapping analysis of H3K27Ac ChIP-seq and RNA-seq showed that the inhibitory effect of SB on the expression of multiple ß cell identity genes was independent of H3K27Ac. SB treatment increased basal oxygen consumption rate (OCR), but attenuated glucose-stimulated OCR in rat islets, without altering the expressions of genes involved in glycolysis and tricarboxylic acid cycle. SB reduced the expression of Kcnj11 (encoding KATP channel) and elevated basal intracellular calcium concentration. On the other hand, SB elicited insulin gene expression in rat islets through increasing H3K18bu occupation in its promoter, without stimulating CREB phosphorylation. These findings indicate that SB potentiates islet function as a lipid molecule at the expense of compromised expression of islet ß cell identity genes.

CBP/p300 HAT maintains the gene network critical for ß cell identity and functional maturity.

Loss of ß cell identity and functional immaturity are thought to be involved in ß cell failure in type 2 diabetes. CREB-binding protein (CBP) and its paralogue p300 act as multifunctional transcriptional co-activators and histone acetyltransferases (HAT) with extensive biological functions. However, whether the regulatory role of CBP/p300 in islet ß cell function depends on the HAT activity remains uncertain. In this current study, A-485, a selective inhibitor of CBP/p300 HAT activity, greatly impaired glucose-stimulated insulin secretion from rat islets in vitro and in vivo. RNA-sequencing analysis showed a comprehensive downregulation of ß cell and α cell identity genes in A-485-treated islets, without upregulation of dedifferentiation markers and derepression of disallowed genes. A-485 treatment decreased the expressions of genes involved in glucose sensing, not in glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. In the islets of prediabetic db/db mice, CBP/p300 displayed a significant decrease with key genes for ß cell function. The deacetylation of histone H3K27 as well as the transcription factors Hnf1α and Foxo1 was involved in CBP/p300 HAT inactivation-repressed expressions of ß cell identity and functional genes. These findings highlight the dominant role of CBP/p300 HAT in the maintenance of ß cell identity by governing transcription network.

Chronic Unpredictable Mild Stress Promotes Atherosclerosis via HMGB1/TLR4-Mediated Downregulation of PPARγ/LXRα/ABCA1 in ApoE-/- Mice.

Background: Although our previous studies have confirmed that the activation of TLR4 is implicated in the development of atherosclerosis induced by chronic unpredicted mild stress (CUMS), the underling mechanism is largely unclear. Here, we hypothesized that CUMS accelerates atherosclerotic development through lowering PPARγ/LXRα-ABCA1 expression via HMGB1/TLR4 signaling. Methods: In present study, CUMS atherosclerotic animal models were established with AopE-/- mice, and CUMS Raw 264.7 macrophage models were mimicked by high corticosterone treatment, These models were treated with Ethyl pyruvate (EP, an inhibitor of HMGB1), TLR4 inhibitor TAK-242, and PPARγ agonist RSG (Rosiglitazone) to test our hypothesis, respectively. Results: Our results indicated that the protein levels of HMGB1, TLR4, and pro-inflammatory cytokines including IL-1ß, TNF-α were elevated with the development of atherosclerosis in CUMS mice, while the expressions of PPARγ, LXRα, and ABCA1 declined. Notably, HMGB1 inhibition by EP reversed CUMS-induced atherosclerotic development, pro-inflammatory cytokines upregulation, and PPARγ/LXRα-ABCA1 downregulation. The same trend was observed in the stressed mice treatment with TAK-242. Further experimental evidences indicated that EP, TAK-242, and RSG treatment notably corrected foam cell formation, HMGB1 release, and down-regulation of LXRα and ABCA1 in CUMS Raw 264.7 macrophage model. Conclusion: These results indicate that CUMS exacerbates atherosclerosis is likely via HMGB1-mediated downregulation of PPARγ/LXRα-ABCA1 through TLR4. These data reveal a novel mechanism by which CUMS aggravates atherosclerosis and may offer a potential therapeutic target for this disease.