RESUMEN
BACKGROUND AND AIMS: NASH is associated with high levels of cholesterol and triglyceride (TG) in the liver; however, there is still no approved pharmacological therapy. Synthesis of cholesterol and TG is controlled by sterol regulatory element-binding protein (SREBP), which is found to be abnormally activated in NASH patients. We aim to discover small molecules for treating NASH by inhibiting the SREBP pathway. APPROACH AND RESULTS: Here, we identify a potent SREBP inhibitor, 25-hydroxylanosterol (25-HL). 25-HL binds to insulin-induced gene (INSIG) proteins, stimulates the interaction between INSIG and SCAP, and retains them in the endoplasmic reticulum, thereby suppressing SREBP activation and inhibiting lipogenesis. In NASH mouse models, 25-HL lowers levels of cholesterol and TG in serum and the liver, enhances energy expenditure to prevent obesity, and improves insulin sensitivity. 25-HL dramatically ameliorates hepatic steatosis, inflammation, ballooning, and fibrosis through down-regulating the expression of lipogenic genes. Furthermore, 25-HL exhibits both prophylactic and therapeutic efficacies of alleviating NASH and atherosclerosis in amylin liver NASH model diet-treated Ldlr-/- mice, and reduces the formation of cholesterol crystals and associated crown-like structures of Kupffer cells. Notably, 25-HL lowers lipid contents in serum and the liver to a greater extent than lovastatin or obeticholic acid. 25-HL shows a good safety and pharmacokinetics profile. CONCLUSIONS: This study provides the proof of concept that inhibiting SREBP activation by targeting INSIG to lower lipids could be a promising strategy for treating NASH. It suggests the translational potential of 25-HL in human NASH and demonstrates the critical role of SREBP-controlled lipogenesis in the progression of NASH by pharmacological inhibition.
Asunto(s)
Insulinas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Lipogénesis/fisiología , Proteínas de Unión a los Elementos Reguladores de Esteroles , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Hígado/metabolismo , Triglicéridos/metabolismo , Colesterol/metabolismo , Lovastatina/metabolismo , Insulinas/metabolismo , Ratones Endogámicos C57BLRESUMEN
New material of the tridensaspid Pterogonaspis yuhaii is described from the Xujiachong Formation in Qujing City, Yunnan Province, revealing the morphology of the ventral side of the headshield for the first time. Most significantly, the cranial anatomy of Pterogonaspis provides the first fossil evidence for the position of the esophagus in galeaspids. The esophagus and dorsal aortae display a central placement in the postbranchial region and do not share a common canal as in osteostracans. Moreover, the paired and symmetrically extending dorsal aortae in galeaspids strikingly resemble those of jawed vertebrates, probably representing a plesiomorphic condition for vertebrates because they are also present in amphioxus and hagfishes. In contrast, the unpaired and asymmetrically extending dorsal aorta in osteostracans is similar to that of lampreys, probably resulting from convergent evolution. In addition, our new data also exhibit some characters that galeaspids uniquely share with osteostracans, such as the complete endoskeletal postbranchial wall and the extensive lateral expansion of the headshield with the marginal arteries and veins.