Discovery of an insulin-induced gene binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting sterol regulatory element-binding protein-mediated lipogenesis.

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.

Pharmacist interventions for persons with intellectual disabilities: A scoping review.

INTRODUCTION: Persons with intellectual disabilities (ID) often have complex health needs due to the development of multiple comorbidities. Given the higher associated use of problematic medications, such as antipsychotics, and polypharmacy, persons with ID may be particularly vulnerable to adverse side effects. With their medication expertise, pharmacists have the potential to address medication related challenges experienced by this population. OBJECTIVE: Explore what is known about the care pharmacists provide to persons with ID. DESIGN: Following Arksey and O'Malley's 5-stage framework for scoping reviews, searches of the PubMed (MEDLINE), Ovid EMBASE, Ovid International Pharmaceutical Abstracts, Scopus and APA PsycINFO databases were conducted in January 2019 with no limits on publication date. Studies of participants diagnosed with ID or healthcare providers/caregivers of persons with ID that referenced a pharmacist care intervention were included. Studies with non-human populations and editorials, commentaries, letters to the editor or discussion papers were excluded. RESULTS: Twenty-six studies were included in the review. Seventy-six pharmacist care interventions were identified in cognitive pharmacy services (n = 46); educational and advisory services (n = 20); and medication prescription processing (n = 10). Fifty-one outcomes were referenced including drug-related interventions (n = 14), drug related problems (n = 9), cost/time-effectiveness (n = 7), secondary symptoms (n = 6), other outcomes (n = 5), general medication usage (n = 4), caregiver and healthcare team satisfaction levels (n = 3), and educational/knowledge (n = 3). CONCLUSION: Pharmacists perform a variety of health care services to persons with ID but the impact of these interventions cannot be accurately measured due to a lack of: 1) universal definitions for ID; 2) reporting of multifactorial conditions contributing to a spectrum of ID severity; and 3) standardized reporting of ID-specific outcomes. Addressing these gaps is necessary for the development of a comprehensive evidence base regarding pharmacist involvement for medication challenges in persons with ID.