Phosphorylation of eIF2α signaling pathway attenuates obesity-induced non-alcoholic fatty liver disease in an ER stress and autophagy-dependent manner

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder and frequently exacerbates in postmenopausal women. In NAFLD, the endoplasmic reticulum (ER) plays an important role in lipid metabolism, in which salubrinal is a selective inhibitor of eIF2α de-phosphorylation in response to ER stress. To determine the potential mechanism of obesity-induced NAFLD, we employed salubrinal and evaluated the effect of ER stress and autophagy on lipid metabolism. Ninety-five female C57BL/6 mice were randomly divided into five groups: standard chow diet, high-fat (HF) diet, HF with salubrinal, HF with ovariectomy, and HF with ovariectomy and salubrinal. All mice except for SC were given HF diet. After the 8-week obesity induction, salubrinal was subcutaneously injected for the next 8 weeks. The expression of ER stress and autophagy markers was evaluated in vivo and in vitro. Compared to the normal mice, the serum lipid level and adipose tissue were increased in obese mice, while salubrinal attenuated obesity by blocking lipid disorder. Also, the histological severity of hepatic steatosis and fibrosis in the liver and lipidosis was suppressed in response to salubrinal. Furthermore, salubrinal inhibited ER stress by increasing the expression of p-eIF2α and ATF4 with a decrease in the level of CHOP. It promoted autophagy by increasing LC3II/I and inhibiting p62. Correlation analysis indicated that lipogenesis in the development of NAFLD was associated with ER stress. Collectively, we demonstrated that eIF2α played a key role in obesity-induced NAFLD, and salubrinal alleviated hepatic steatosis and lipid metabolism by altering ER stress and autophagy through eIF2α signaling.

Salubrinal induces fetal hemoglobin expression via the stress-signaling pathway in human sickle erythroid progenitors and sickle cell disease mice

“…SAL is under development for hepatic steatosis by altering cellular stress and autophagy through eIF2α signaling [ 46 ], treatment of osteogenesis imperfect [ 47 ], and SAL efficiently blocked osteoporosis in mice [ 48 ]. To move SAL to clinical trials an oral formulation is required; mice have been treated with SAL in soymilk, which restored primordial follicles production in galactosemia mice [ 49 ].…”

Salubrinal induces fetal hemoglobin expression via the stress-signaling pathway in human sickle erythroid progenitors and sickle cell disease mice

“…SAL is under development for other diseases such as hepatic steatosis by altering cellular stress and autophagy through eIF2α signaling (44), treatment of osteogenesis imperfect (45), and SAL efficiently blocked osteoporosis in mice (46). To move SAL to clinical trials an oral formulation is required; mice have been treated with SAL in soymilk, which restored primordial follicles production in galactosemia mice (47) however, the design of novel and safer alternatives for HU is highly desirable for people with SCD.…”

2-Amino-3-Methylimidazo[4,5-f]quinoline Triggering Liver Damage by Inhibiting Autophagy and Inducing Endoplasmic Reticulum Stress in Zebrafish (Danio rerio)

“…ER stress has long been recognized as one of the autophagy inducers [36], which can regulate autophagy through different UPR signaling pathways (Figure 6) [22]. The previous research confirmed that autophagy plays a pivotal role in various forms of liver damage [37][38][39][40]. However, there is no study about autophagy in liver after IQ exposure.…”