Protective Effect of Gomisin N against Endoplasmic Reticulum Stress-Induced Hepatic Steatosis

Abstract

Gomisin N is a physiological substance derived from Schisandra chinensis. In the present study, the in vitro and in vivo effects of gomisin N on endoplasmic reticulum (ER) stress and hepatic steatosis were investigated. We quantified the expression of markers of ER stress, including glucose regulated protein 78 (GRP78), CCAAT/enhancer binding protein (C/EBP) homolog protein (CHOP), and X-box-binding protein-1 (XBP-1), and triglyceride (TG) accumulation, in HepG2 cells treated with tunicamycin or palmitate. Tunicamycin treatment in HepG2 cells induced expression of markers of ER stress and increased TG levels; Gomisin N reversed these effects, reducing the expression of markers of ER stress and TG levels. Similar effects were seen following palmitate pretreatment of HepG2 cells. The inhibitory effects of gomisin N were further confirmed in mice injected with tunicamycin. Gomisin N reduced expression of markers of ER stress and decreased TG levels in mouse liver after tunicamycin injection. Furthermore, gomisin N decreased expression of inflammatory and lipogenic genes in palmitate-incubated HepG2 cells. These results suggest that gomisin N inhibits ER stress and ameliorates hepatic steatosis induced by ER stress. Key words gomisin N; endoplasmic reticulum (ER) stress; hepatic steatosis; lipogenesis; inflammationThe endoplasmic reticulum (ER) plays critical roles in the synthesis of secreted and membrane proteins by mediating protein folding, production of lipids and sterols, and the storage of intracellular Ca 2+ . 1) However, pathological factors that disrupt ER homeostasis lead to the accumulation of unfolded protein in the ER lumen, provoking ER stress. Cells usually survive early stress by attenuating protein translation, removing unfolded proteins, and upregulating protein chaperons via the unfolded protein response (UPR).1) However, prolonged ER stress can lead to cell death and cause several diseases including ischemia/reperfusion injury, heart disease, and diabetes. [2][3][4][5] Recent studies show that hepatic ER stress is observed in metabolic diseases such as obesity and diabetes.2-5) ER stress contributes to development of insulin resistance and hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). [6][7][8][9]

Gomisin N inhibits adipogenesis and prevents high-fat diet-induced obesity

“…GN is a phytochemical lignan isolated from S. chinensis 17. Previously, we have reported that GN showed a protective effect against ER stress-induced hepatosteatosis22. In the present study, we demonstrated that GN inhibited the differentiation of 3T3-L1 preadipocytes, primarily through the impairment of the MCE process, during the early stage of adipocyte differentiation.…”

“…Gomisin N (GN) is a lignan from S. chinensis and was reported to exhibit hepatoprotective18, anticancer19, and anti-inflammatory effects20. Very recently, we have reported that S. chinensis and GN show protective effects against the endoplasmic reticulum (ER) stress-induced hepatic steatosis2122.…”

Schisandrin B: A Double‐Edged Sword in Nonalcoholic Fatty Liver Disease

“…A further clinical study is worthwhile to conduct in an effort to confirm the beneficial effect of aqueous extracts of FSC (as well as Sch B) in obese individuals. The ability of Sch B to ameliorate hepatic steatosis in cultured HepG2 hepatocytes and in C57BL/6 mouse liver in relation to the protection against ER stress has recently been reported [82]. Gomisin N (a stereoisomer of Sch B) was found to reduce the expression of ER stress markers (such as glucose-regulated protein-78, CCAAT/enhancer binding protein homolog protein, and X-box-binding protein-1), proinflammatory cytokines, and lipogenic enzymes and the level of TG in palmitate-challenged HepG2 cells [82].…”

“…The ability of Sch B to ameliorate hepatic steatosis in cultured HepG2 hepatocytes and in C57BL/6 mouse liver in relation to the protection against ER stress has recently been reported [82]. Gomisin N (a stereoisomer of Sch B) was found to reduce the expression of ER stress markers (such as glucose-regulated protein-78, CCAAT/enhancer binding protein homolog protein, and X-box-binding protein-1), proinflammatory cytokines, and lipogenic enzymes and the level of TG in palmitate-challenged HepG2 cells [82]. Results from the cell-based study were further confirmed by an animal study, in which gomisin N was found to suppress the expression of ER stress markers and the levels of hepatic TG and TC in tunicamycin (an ER stress inducer)-injected mice [82].…”

“…Gomisin N (a stereoisomer of Sch B) was found to reduce the expression of ER stress markers (such as glucose-regulated protein-78, CCAAT/enhancer binding protein homolog protein, and X-box-binding protein-1), proinflammatory cytokines, and lipogenic enzymes and the level of TG in palmitate-challenged HepG2 cells [82]. Results from the cell-based study were further confirmed by an animal study, in which gomisin N was found to suppress the expression of ER stress markers and the levels of hepatic TG and TC in tunicamycin (an ER stress inducer)-injected mice [82]. In addition, Sch B was found to inhibit cell proliferation and induce apoptosis in cultured human hepatoma SMMC-7721 cells via a caspase-3-dependent pathway [88].…”