ARHGAP21 deficiency impairs hepatic lipid metabolism and improves insulin signaling in lean and obese mice

Abstract

ARHGAP21 is a Rho-GAP that controls GTPases activity in several tissues, but its role on liver lipid metabolism is unknown. Thus, to achieve the Rho-GAP role in the liver, control and ARHGAP21-haplodeficient mice were fed chow (Ctl and Het) or high-fat diet (Ctl-HFD and Het-HFD) for 12 weeks, and pyruvate and insulin tolerance tests, insulin signaling, liver glycogen and triglycerides content, gene and protein expression, and very-low-density lipoprotein secretion were measured. Het mice displayed reduced body weight and plasma triglycerides levels, and increased liver insulin signaling. Reduced gluconeogenesis and increased glycogen content were observed in Het-HFD mice. Gene and protein expression of microsomal triglyceride transfer protein were reduced in both Het mice, while the lipogenic genes SREBP-1c and ACC were increased. ARHGAP21 knockdown resulted in hepatic steatosis through increased hepatic lipogenesis activity coupled with decreases in CPT1a expression and very-low-density lipoprotein export. In conclusion, liver of ARHGAP21-haplodeficient mice are more insulin sensitive, associated with higher lipid synthesis and lower lipid export.

ARHGAP21 Acts as an Inhibitor of the Glucose-Stimulated Insulin Secretion Process

“…ARHGAP21 heterozygotes mice presented an increased expression of UCP1 in BAT (Brown Adipose Tissue) (8), and increased of SREBP-1C and ACC gene expression in liver. In addition, these mice presented a reduction in CPT1a gene expression in liver (9). Therefore, based on this, we are tempted to speculate that ARHGAP21 also may affect lipids metabolism in pancreatic bcells and consequently reduces insulin secretion.…”

“…• For experiments involving hypo insulin-secreting mice: [8][9][10][11][12] weeks old male Swiss mice, acquired from the State University of Campinas, were maintained on a 12 h light-dark cycle at 20-21°C, with controlled humidity during the entire experiment and fed with a standard CHOW diet and offered tap water ad libitum. Mice were randomly assigned to a sedentary control group (CTL), which limited to typical movement inside the cages, and the endurance-training group (T).…”

“…Thus, investigating proteins and process that can mitigate beta cell overload and dysfunction may reveal new targets for better management of this pathology. In this context, our group has explored the role of ARGHAP21 (a RhoGAP protein), that has been implicated in cancer due to its suppressor tumor function, (4,5), and in the glycemic and insulin homeostasis (6)(7)(8)(9).…”

A comprehensive transcriptomic landscape of cholangiocarcinoma based on bioinformatics analysis from large cohort of patients

“…For the upregulated DEGs, ARHGAP21 was the only gene whose expression was found significantly positively related to both patient OS and DFS. ARHGAP21 functions preferentially as a GTPase-activating protein (GAP) for CDC42 and regulates the ARP2/3 complex and F-actin dynamics at the Golgi through control of CDC42 activity 26 . Evidence showed that as a PDZ domain containing protein, ARHGAP21 could interact with the PDZ-binding motif of Claudin-2, in such way promoted breast cancer liver metastasis 27 .…”

Energy homeostasis deregulation is attenuated by TUDCA treatment in streptozotocin-induced Alzheimer’s disease mice model

“…Western blot analysis was performed as previously described 33 . Briefly, hypothalamus and BAT samples were homogenized in lysis buffer and centrifuged (12,000 g for 20 min at 4 °C) to obtain a protein extract.…”