Background & Aims: Liver fibrosis is a pivotal pathology in multiple hepatic disease indications, profoundly characterizing disease severity and outcomes. The role of activin B, a TGFβ superfamily cytokine, in liver health and disease is largely unknown. We aimed to investigate whether activin B modulates liver fibrogenesis. Methods: Liver and serum activin B, along with its analog activin A, were analyzed in patients with liver fibrosis from different etiologies and in mouse acute and chronic liver injury models. Activin B, activin A, or both was immunologically neutralized in mice with progressive or established carbon tetrachloride (CCl4)-induced liver fibrosis. The direct effects of activin B and A on hepatocytes and hepatic stellate cells (HSCs) were evaluated in vitro. Results: As a result, hepatic and circulating activin B was increased in human patients with liver fibrosis caused by several liver diseases. In mice, hepatic and circulating activin B exhibited persistent elevation following the onset of several types of liver injury, whereas activin A displayed transient increases. The results revealed a close correlation of activin B with liver injury regardless of etiology and species. We found that neutralizing activin B largely prevented, as well as remarkably regressed, CCl4-induced liver fibrosis, which was augmented by co-neutralizing activin A. Mechanistically, activin B directly promotes hepatocyte death, induces a profibrotic expression profile in HSCs, and stimulates HSCs to form a septa structure. In addition, activin B and A interdependently upregulated the transcription of profibrotic factors including connective tissue growth factor and TGFβ1 in injured livers. Conclusions: We demonstrate that activin B, cooperating with activin A, directly acts on multiple liver cell populations, and drives the initiation and progression of liver fibrosis. Our finding inspires the development of a novel therapy of chronic liver diseases.

Gastric electrical stimulation (GES) of the stomach is an effective treatment of nausea and vomiting in patients with gastroparesis (Gastroenterology 125: 421–28, 2003). However, the mechanism is unclear, as many patients show resolution of nausea and vomiting yet continue to exhibit delayed gastric emptying. This suggests GES may relieve symptoms by activation of a mechanism involving the central nervous system. The purpose of this study was to determine whether GES produces changes in the brain evidenced by alterations in cerebral blood flow on positron emission tomography (PET). Eight patients (6 females, 2 males) ranging in age from 27 to 68 yr were studied. Each patient had profound gastroparesis and had undergone implantation of a GES device from 6 to 57 mo (mean 25) prior. All patients studied had significant improvement in symptoms of nausea, vomiting, and early satiety after implantation of the GES device. PET scans were performed after an overnight fast and with the GES device in the ON mode. Each patient was then given an IV injection 30–40 mCi O15‐water. After PET image data were obtained the GES device was then turned to the OFF mode for 30 min. The O15‐water injection and PET image scanning was then repeated. Respective PET images obtained with the GES device in the ON and OFF modes were then analyzed and compared. PET images were analyzed using SPM2 (Statistical Parametric Mapping), implemented using Matlab 6.5 Prior to statistical analysis all images were realigned to correct motion movements and spatially normalized into the MNI standard template to remove inter‐subject anatomical variability. Spatially normalized images were smoothed using an isotropic Gaussian kernel with 16 mm FWHM to increase the signal‐to‐noise ratio. Statistical comparisons between ON and OFF scans were performed on a voxel‐by‐voxel basis using paired t statistics. Significant voxels were superimposed on a high resolution MRI template provided by SPM2, thus allowing anatomical identification. Significant increases in blood flow during GES were noted in the middle, superior, and inferior gyri, in the middle occipital and middle temporal gyri, and in the amygdala and parahippocampal gyri (P < 0.05 for each locus, respectively). Likewise, significant decreases in blood flow during GES were noted in the pre and post central gyri, in the anterior cingulate gyri, and in the caudate head and putamen (p < 0.05 for each locus, respectively). Conclusions:  1) GES produces significant alterations in cerebral blood flow in gastroparetic patients; 2) central nervous system mechanisms during GES may be responsible for the relief of nausea and vomiting in these patients.