Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation.

Metabolic (dysfunction)-associated steatohepatitis (MASH) is the advanced stage of metabolic (dysfunction)-associated fatty liver disease (MAFLD) lacking approved clinical drugs. Adenosine A1 receptor (A1R), belonging to the G-protein-coupled receptors (GPCRs) superfamily, is mainly distributed in the central nervous system and major peripheral organs with wide-ranging physiological functions; however, the exact role of hepatic A1R in MAFLD remains unclear. Here, we report that liver-specific depletion of A1R aggravates while overexpression attenuates diet-induced metabolic-associated fatty liver (MAFL)/MASH in mice. Mechanistically, activation of hepatic A1R promotes the competitive binding of sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) to sequestosome 1 (SQSTM1), rather than protein kinase A (PKA) leading to SCAP degradation in lysosomes. Reduced SCAP hinders SREBP1c/2 maturation and thus suppresses de novo lipogenesis and inflammation. Higher hepatic A1R expression is observed in patients with MAFL/MASH and high-fat diet (HFD)-fed mice, which is supposed to be a physiologically adaptive response because A1R agonists attenuate MAFL/MASH in an A1R-dependent manner. These results highlight that hepatic A1R is a potential target for MAFL/MASH therapy.

Deep brain stimulation on the external segment of the globus pallidus improves the electrical activity of internal segment of globus pallidus in a rat model of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the progressive degeneration of neurons in the substantia nigra pars compacta. Deep brain stimulation (DBS) is an effective treatment for PD cardinal motor symptoms. DBS of GPe has been recognized as an effective treatment option for motor symptoms of PD, but the mechanism is still essentially unknown. To investigate the impact of DBS in the external segment of globus pallidus (GPe) on the pathway of the basal ganglia (BG), we recorded the electrical activities of single neurons and local field potential (LFP) of the internal segment of globus pallidus (GPi). The results showed that the firing rate of GPi neurons in the 6-OHDA lesioned rats returned to the normal level after GPe-DBS for two weeks. Moreover, the CV value of GPi neurons is significantly lower than that in the PD group. The different frequency bands of GPi LFP in PD rats have improved correspondingly. These findings indicate that the improvement of the electrical activity of GPi by GPe-DBS in PD rats may be an important electrophysiological mechanism for treating PD.