NOX2 activated by α₁-adrenoceptors modulates hepatic metabolic routes stimulated by β-adrenoceptors

Abstract

The NADPH oxidase (NOX) family of enzymes oxidase catalyzes the transport of electrons from NADPH to molecular oxygen and generates O(2)(•-), which is rapidly converted into H(2)O(2). We aimed to identify in hepatocytes the protein NOX complex responsible for H(2)O(2) synthesis after α(1)-adrenoceptor (α(1)-AR) stimulation, its activation mechanism, and to explore H(2)O(2) as a potential modulator of hepatic metabolic routes, gluconeogenesis, and ureagenesis, stimulated by the ARs. The dormant NOX2 complex present in hepatocyte plasma membrane (HPM) contains gp91(phox), p22(phox), p40(phox), p47(phox), p67(phox) and Rac 1 proteins. In HPM incubated with NADPH and guanosine triphosphate (GTP), α(1)-AR-mediated H(2)O(2) synthesis required all of these proteins except for p40(phox). A functional link between α(1)-AR and NOX was identified as the Gα(13) protein. Alpha(1)-AR stimulation in hepatocytes promotes Rac1-GTP generation, a necessary step for H(2)O(2) synthesis. Negative cross talk between α(1)-/β-ARs for H(2)O(2) synthesis was observed in HPM. In addition, negative cross talk of α(1)-AR via H(2)O(2) to β-AR-mediated stimulation was recorded in hepatocyte gluconeogenesis and ureagenesis, probably involving aquaporine activity. Based on previous work we suggest that H(2)O(2), generated after NOX2 activation by α(1)-AR lightening in hepatocytes, reacts with cAMP-dependent protein kinase A (PKA) subunits to form an oxidized PKA, insensitive to cAMP activation that prevented any rise in the rate of gluconeogenesis and ureagenesis.

Hepatocytes produce TNF-α following hypoxia-reoxygenation and liver ischemia-reperfusion in a NADPH oxidase- and c-Src-dependent manner

“…4D). It is presently unclear whether Rac2 can partially compensate for the lack of Rac1 in hepatocytes, but this appears unlikely given that only Rac1, but not Rac2, is found in hepatocyte plasma membranes (5). Despite the fact that Rac2 deletion alone failed to attenuate acute-phase TNF-␣ following I/R, Rac2 and NOX2 in the Kupffer cell certainly play a role in modulating the TNF-␣ response.…”

“…Both NOX1 and NOX2, as well as Rac1, have been identified in hepatocytes (5). Rac1 was also shown to be required for the recruitment of c-Src to NOX-active endosomes following H/R in cell line studies that used Rac1-siRNA knockdown (28).…”

Renal Denervation Reverses Hepatic Insulin Resistance Induced by High-Fat Diet

“…Diaz-Cruz et al (28) demonstrated that activation of α-1 ADR inhibits β-ADR–stimulated pathways through NOX2 activation. Together, the current results suggest suppression of hepatic gluconeogenesis with RDN surgery through α-1 ADR, natriuretic peptides, and the LXR-α pathway.…”

The ROS-generating and antioxidant systems in the liver of rats treated with prednisolone and vitamin D(3)

“…Основним про-дуктом функціонування NAD(P)H-оксидази є супероксидний аніон-радикал, який виявляє бактерицидну дію та є одним із найважливіших компонентів неспецифічного протиінфекційного захисту організму. Крім того, NAD(P)H-оксидаза експресується в гепатоцитах та зірчастих клітинах печінки [46,47]. Незважаючи на важ-ливу роль NAD(P)H-оксидази в генеруванні вільнорадикальних форм кисню, одержані ре-зультати дослідження показали, що активність ензиму в гомогенаті печінки не тільки не зростає, але навіть знижується на 55% (Р < 0,05) за дії преднізолону порівняно з контролем (табл.…”