High fat diet-induced downregulation of TRPV2 mediates hepatic steatosis via p21 signalling

The global prevalence and incidence of non-alcoholic fatty liver disease (NAFLD) are exhibiting an increasing trend. NAFLD is characterized by a significant accumulation of lipids, though its underlying mechanism is still unknown. Here we report that high-fat diet (HFD) feeding induced hepatic steatosis in mice, which was accompanied by a reduction in the expression and function of hepatic TRPV2. Moreover, conditional knockout of TRPV2 in hepatocytes exacerbated HFD-induced hepatic steatosis. In an in vitro model of NAFLD, TRPV2 regulated lipid accumulation in HepG2 cells, and TRPV2 activation inhibited the expression of the cellular senescence markers p21 and p16, all of which were mediated by AMPK phosphorylation. Finally, we found that administration of probenecid, a TRPV2 agonist, impaired HFD-induced hepatic steatosis and suppressed HFD-induced elevation in p21 and p16. Collectively, our findings imply that hepatic TRPV2 protects against the accumulation of lipids by modulating p21 signalling. (AU)

High fat diet-induced downregulation of TRPV2 mediates hepatic steatosis via p21 signalling

The global prevalence and incidence of non-alcoholic fatty liver disease (NAFLD) are exhibiting an increasing trend. NAFLD is characterized by a significant accumulation of lipids, though its underlying mechanism is still unknown. Here we report that high-fat diet (HFD) feeding induced hepatic steatosis in mice, which was accompanied by a reduction in the expression and function of hepatic TRPV2. Moreover, conditional knockout of TRPV2 in hepatocytes exacerbated HFD-induced hepatic steatosis. In an in vitro model of NAFLD, TRPV2 regulated lipid accumulation in HepG2 cells, and TRPV2 activation inhibited the expression of the cellular senescence markers p21 and p16, all of which were mediated by AMPK phosphorylation. Finally, we found that administration of probenecid, a TRPV2 agonist, impaired HFD-induced hepatic steatosis and suppressed HFD-induced elevation in p21 and p16. Collectively, our findings imply that hepatic TRPV2 protects against the accumulation of lipids by modulating p21 signalling. (AU)

High fat diet-induced downregulation of TRPV2 mediates hepatic steatosis via p21 signalling.

The global prevalence and incidence of non-alcoholic fatty liver disease (NAFLD) are exhibiting an increasing trend. NAFLD is characterized by a significant accumulation of lipids, though its underlying mechanism is still unknown. Here we report that high-fat diet (HFD) feeding induced hepatic steatosis in mice, which was accompanied by a reduction in the expression and function of hepatic TRPV2. Moreover, conditional knockout of TRPV2 in hepatocytes exacerbated HFD-induced hepatic steatosis. In an in vitro model of NAFLD, TRPV2 regulated lipid accumulation in HepG2 cells, and TRPV2 activation inhibited the expression of the cellular senescence markers p21 and p16, all of which were mediated by AMPK phosphorylation. Finally, we found that administration of probenecid, a TRPV2 agonist, impaired HFD-induced hepatic steatosis and suppressed HFD-induced elevation in p21 and p16. Collectively, our findings imply that hepatic TRPV2 protects against the accumulation of lipids by modulating p21 signalling.

Three-Day Continuous Oxytocin Infusion Attenuates Thermal and Mechanical Nociception by Rescuing Neuronal Chloride Homeostasis via Upregulation KCC2 Expression and Function.

Oxytocin (OT) and its receptor are promising targets for the treatment and prevention of the neuropathic pain. In the present study, we compared the effects of a single and continuous intrathecal infusion of OT on nerve injury-induced neuropathic pain behaviours in mice and further explore the mechanisms underlying their analgesic properties. We found that three days of continuous intrathecal OT infusion alleviated subsequent pain behaviours for 14 days, whereas a single OT injection induced a transient analgesia for 30 min, suggesting that only continuous intrathecal OT attenuated the establishment and development of neuropathic pain behaviours. Supporting this behavioural finding, continuous intrathecal infusion, but not short-term incubation of OT, reversed the nerve injury-induced depolarizing shift in Cl- reversal potential via restoring the function and expression of spinal K+-Cl- cotransporter 2 (KCC2), which may be caused by OT-induced enhancement of GABA inhibitory transmission. This result suggests that only continuous use of OT may reverse the pathological changes caused by nerve injury, thereby mechanistically blocking the establishment and development of pain. These findings provide novel evidence relevant for advancing understanding of the effects of continuous OT administration on the pathophysiology of pain.