Therefore, the suppression of miR-122 likely results in increased SREBP-2 activation, which constitutes an additional
pathway of increased SREBP-2 activation in human NASH. In this edition of The Journal of Gastroenterology and Hepatology, Zhao and colleagues describe the effect of inflammation on hepatic SREBP-2, and subsequent LDLR and HMGR expression in both in vivo and in vitro systems.13 Chronic low-grade inflammation and cytokine stimulation (interleukin [IL]-1β and IL-6) triggered SREBP-2 activation and increased hepatic LDLR receptor expression, in addition to enhancing HMG-CoA reductase activity, culminating in increased hepatic cholesterol (free and esterified) levels. Furthermore, Fulvestrant order chronic low-grade inflammation was found to interfere with the feedback mechanism responsible for decreasing nuclear SREBP-2 in the presence of heightened intracellular FC levels, thereby deregulating cholesterol homeostasis. Subcutaneous casein injections in C57Bl/6J mice induced both IL-6 and serum amyloid A protein (similar to human C-reactive protein), simultaneously INCB024360 molecular weight increasing LDLR and HMGR expression, in addition to nuclear SREBP-2 levels. Similar results were obtained in human HepG2 cells. Following IL-1β and IL-6 exposure, expression of LDLR and
HMGR increased. Both in vivo and in vitro experimental approaches were found to increase hepatic intracellular cholesterol and esterified lipids (triglycerides and cholesteryl esters), confirming that the molecular changes in cholesterol uptake and biosynthesis did lead to changes in lipid molecule accumulation. Further selleck chemical compounding SREBP-2 involvement in NASH, hyperinsulinemia, a common component of the pathophysiology of NASH that stems from insulin resistance, also increases hepatic SREBP-2 in mice by an intracellular signaling pathway, in a manner that is thought to involve extracellular signal-regulated
kinases (ERK)-1 and ERK-2.14 These findings provide a potential explanation for the close relationship between insulin resistance (and resulting hyperinsulinemia), dyslipidemia, and atheroma, and therefore, why NASH is such a strong risk factor for cardiovascular disease. In addition, there is a deepening relationship between metabolic factors and cytokines, as mediators of both insulin resistance and hepatic lipid metabolism. For instance, macrophage inflammatory protein-1, which may be related to adipose and liver inflammation in metabolic syndrome, is known to activate the lipogenic transcription factor SREBP-1, at least in vitro, thereby potentially aggravating hepatic steatosis. Further, tumor necrosis factor-α and IL-6, circulating products of adipose macrophages, have been implicated in the pathogenesis of hepatic insulin resistance, for example, by induction of suppressor of cytokine signaling-3, which blocks insulin receptor signaling pathways.