Deficiency of suppressor enhancer Lin12 1 like (SEL1L) in mice leads to systemic endoplasmic reticulum stress and embryonic lethality.

Stress in the endoplasmic reticulum (ER) plays an important causal role in the pathogenesis of several chronic diseases such as Alzheimer, Parkinson, and diabetes mellitus. Insight into the genetic determinants responsible for ER homeostasis will greatly facilitate the development of therapeutic strategies for the treatment of these debilitating diseases. Suppressor enhancer Lin12 1 like (SEL1L) is an ER membrane protein and was thought to be involved in the quality control of secreted proteins. Here we show that the mice homozygous mutant for SEL1L were embryonic lethal. Electron microscopy studies revealed a severely dilated ER in the fetal liver of mutant embryos, indicative of alteration in ER homeostasis. Consistent with this, several ER stress responsive genes were significantly up-regulated in the mutant embryos. Mouse embryonic fibroblast cells deficient in SEL1L exhibited activated unfolded protein response at the basal state, impaired ER-associated protein degradation, and reduced protein secretion. Furthermore, markedly increased apoptosis was observed in the forebrain and dorsal root ganglions of mutant embryos. Taken together, our results demonstrate an essential role for SEL1L in protein quality control during mouse embryonic development.

The Changing Landscape of Diabetes Therapy for Cardiovascular Risk Reduction: JACC State-of-the-Art Review.

Type 2 diabetes mellitus (T2D) is a major risk factor for cardiovascular disease (CVD), the most common cause of death in T2D. Despite improved risk factor control, however, adults with T2D continue to experience substantial excess CVD risk. Until recently, however, improved glycemic control has not been associated with robust macrovascular benefit. The advent of 2 new classes of antihyperglycemic agents, the sodium-glucose cotransporter-2 inhibitors and the glucagon-like peptide-1 receptor agonists, and their respective large cardiovascular outcome trials, has led to a paradigm shift in how cardiologists and heath care practitioners conceptualize T2D treatment. Herein, the authors review the recent trial evidence, the potential mechanisms of action of the sodium-glucose cotransporter-2 inhibitors and the glucagon-like peptide-1 receptor agonists, safety concerns, and their use for the primary prevention of CVD as well as in diabetic patients with impaired renal function and heart failure.