DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling.

The dedicator of cytokinesis 5 (DOCK5) is associated with obesity. However, the mechanism by which DOCK5 contributes to obesity remains completely unknown. Here, we show that hepatic DOCK5 expression significantly decreases at a state of insulin resistance (IR). Deletion of DOCK5 in mice reduces energy expenditure, promotes obesity, augments IR, dysregulates glucose metabolism, and activates the mTOR (Raptor)/S6K1 pathway under a high-fat diet (HFD). The overexpression of DOCK5 in hepatocytes inhibits gluconeogenic gene expression and increases the level of insulin receptor (InsR) and Akt phosphorylation. DOCK5 overexpression also inhibits mTOR/S6K1 phosphorylation and decreases the level of raptor protein expression. The opposite effects were observed in DOCK5-deficient hepatocytes. Importantly, in liver-specific Raptor knockout mice and associated hepatocytes, the effects of an adeno-associated virus (AAV8)- or adenovirus-mediated DOCK5 knockdown on glucose metabolism and insulin signaling are largely eliminated. Additionally, DOCK5-Raptor interaction is indispensable for the DOCK5-mediated regulation of hepatic glucose production (HGP). Therefore, DOCK5 acts as a regulator of Raptor to control hepatic insulin activity and glucose homeostasis.

Sfrp5 interacts with Slurp1 to regulate the accumulation of triglycerides in hepatocyte steatosis model.

Secreted frizzled-related protein 5 (Sfrp5), an anti-inflammatory adipocytokine secreted by adipocytes, plays an important role in energy metabolism. Studies have shown that Sfrp5 plays a salutary role in the regulation of lipid metabolism, but its specific mechanism needs further study. In this study, we showed a lower level of Sfrp5 in subjects with diet-induced obesity than in normal-diet C57BL/6J mice. To further investigate Sfrp5-associated proteins in HepG2 cells, the immunoprecipitation assay and silver staining assay were performed. By mass spectrometry analysis, secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide (Slurp-1) was found to interact with Sfrp5. Further verification was obtained through the positive and reverse immunoprecipitation assay. In this study, we found that the sole over-expression of Slurp1 promoted the expression of Sfrp5 in palmitate-induced HepG2 cells. In addition, our experimental evidence shows that the role of Slurp1 in decreasing TG level was greatly reduced in the case of suppression of expression of Sfrp5 in palmitate-induced model cells. Our study further found that Slurp1 regulates the synthesis pathway of triglyceride by interacting with Sfrp5 to alleviate triglyceride accumulation in palmitate-induced model cells. In summary, we are the first to discover the interaction between Sfrp5 and Slurp1, and we found that Slurp1 may regulate the accumulation of TG through Sfrp5.

GNG2 acts as a tumor suppressor in breast cancer through stimulating MRAS signaling.

G-protein gamma subunit 2 (GNG2) is involved in several cell signaling pathways, and is essential for cell proliferation and angiogenesis. However, the role of GNG2 in tumorigenesis and development remains unclear. In this study, 1321 differentially expressed genes (DEGs) in breast cancer (BC) tissues were screened using the GEO and TCGA databases. KEGG enrichment analysis showed that most of the enriched genes were part of the PI3K-Akt signaling pathway. We identified GNG2 from the first five DEGs, its expression was markedly reduced in all BC subtype tissues. Cox regression analysis showed that GNG2 was independently associated with overall survival in patients with luminal A and triple-negative breast cancers (TNBC). GNG2 over-expression could significantly block the cell cycle, inhibit proliferation, and promote apoptosis in BC cells in vitro. In animal studies, GNG2 over-expression inhibited the growth of BC cells. Further, we found that GNG2 significantly inhibited the activity of ERK and Akt in an MRAS-dependent manner. Importantly, GNG2 and muscle RAS oncogene homolog (MRAS) were co-localized in the cell membrane, and the fluorescence resonance energy transfer (FRET) experiment revealed that they had direct interaction. In conclusion, the interaction between GNG2 and MRAS likely inhibits Akt and ERK activity, promoting apoptosis and suppressing proliferation in BC cells. Increasing GNG2 expression or disrupting the GNG2-MRAS interaction in vivo could therefore be a potential therapeutic strategy to treat BC.