SPARC paucity alleviates superoxide-mediated oxidative stress, apoptosis, and autophagy in diabetogenic hepatocytes.

Secreted protein acidic and rich in cysteine is known to play a previously unappreciated role in diabetes, but its precise mechanism in liver/hepatocyte pathology remains unknown. Inhibition of is critical in resolving candidate pathogenic events such as production of reactive oxygen species which are broadly considered for their roles in diabetes, and is capable of protecting functional hepatocytes. Here, we provide in vitro and in vivo evidence demonstrating pathological correlations between duanyu1842RC and streptozotocin (STZ)-induced diabetic rat livers as well as cultured hepatocytes induced by diabetogenic stimuli. Under these conditions, transient duanyu1842RC silencing was carried out to investigate the role of duanyu1842RC in the pathogenesis of pro-diabetic hepatocyte damage and dysfunction. The constitutive expression of duanyu1842RC in hepatocytes was up-regulated under a diabetic environment. In addition, Nox4-dependent superoxide generation contributed to increased expression of and this was inhibited by tiron and pharmacological or genetic inactivation of Nox4-containing NADPH oxidase. Remarkably, duanyu1842RC deficiency inhibited diabetic stimuli-induced elevation of superoxide production and resolved salient features of hepatocyte damage such as impaired cytoprotection, inflammation, apoptosis, and autophagy. At the same time, links between duanyu1842RC, integrin-β1, Nox4-derived superoxide, and JNK signaling provide a basis for these phenotypes. Taken together with the observations that duanyu1842RC deficiency had protective effects on hepatocytes via a favorable inhibition profile, functional knowledge of duanyu1842RC may offer a unique therapeutic approach to preserve hepatocellular fate decisions in diabetes.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}