Hepatic stellate cells (HSCs) store retinoids and triacylglycerols in cytoplasmic lipid droplets. Two prominent features of HSC activation in liver fibrosis are loss of lipid droplets along with increase of α-smooth muscle actin (α-SMA), but the link between these responses and HSC activation remains elusive. In non-adipose cells, adipose differentiation-related protein (ADRP) coats lipid droplets and regulates their formation and lipolysis; however its function in HSCs is unknown. Here, we observed, in human liver sections or primary HSC culture, ADRP localization to lipid droplets of HSCs, and reduced staining coincident with loss of lipid droplets in liver fibrosis and in culture-activated HSCs, consistent with HSC activation. In the LX-2 human immortalized HSCs, with scant lipid droplets and features of activated HSCs, we found that the upregulation of ADRP mRNA by palmitate is potentiated by retinol, accompanied by increased ADRP protein, generation of retinyl palmitate and lipid droplet formation. ADRP induction also led to decreased expression of α-SMA mRNA and its protein, while ADRP knockdown with small interfering RNA (siRNA) normalized α-SMA expression. Furthermore, ADRP induction by retinol and palmitate resulted in decreased expression of collagen I and matrix metalloproteinase-2 mRNA, fibrogenic genes associated with activated HSCs, while increasing matrix metalloproteinase-1 mRNA; ADRP knockdown with siRNA reversed these changes. Tissue inhibitor of metalloproteinase-1 was not affected. Thus, ADRP upregulation mediated by retinol and palmitate promotes downregulation of HSC activation and is functionally linked to the expression of fibrogenic genes.
At the mild to moderate level of sedation studied, midazolam and propofol sedation resulted in the same propensity for UAO. In this homogeneous group of healthy subjects, there was a considerable range of negative pressures required to cause UAO. The specific factors responsible for the maintenance of the upper airway during sedation remain to be elucidated.
Perianal fistulizing disease is an aggressive and debilitating phenotype of Crohn's disease (CD), representing a significant therapeutic challenge. New work has led to advancement in epidemiology and long-term outcomes of perianal disease. The range of therapeutic options continues to expand, including new biologic agents, biosimilars, and stem cell therapy. Areas covered: We discuss updates to all aspects of management of perianal disease, with a focus on the last 3 years of published data. Areas considered include new data on epidemiology and prognostication, medical and surgical therapy, and stem cell therapy. Expert commentary: The presence of perianal disease at CD diagnosis portends a significantly worse disease course. Patients with perianal disease require close monitoring to identify those who are at risk for worsening disease, suboptimal biologic drug levels, and signs of developing neoplasm. With the impending availability of local mesenchymal stem cell therapy, this becomes increasingly important as this therapy, although extremely promising, is thus far only effective in patients without proctitis.
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