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The DHCR7 enzyme converts 7-DHC into cholesterol. Mutations in DHCR7 can block cholesterol production, leading to abnormal accumulation of 7-DHC and causing Smith–Lemli–Opitz syndrome (SLOS). SLOS is an autosomal recessive disorder characterized by multiple malformations, including microcephaly, intellectual disability, behavior reminiscent of autism, sleep disturbances, and attention-deficit/hyperactivity disorder (ADHD)-like hyperactivity. Although 7-DHC affects neuronal differentiation in ex vivo experiments, the precise mechanism of SLOS remains unclear. We generated Dhcr7 deficient (dhcr7 −/− ) zebrafish that exhibited key features of SLOS, including microcephaly, decreased neural stem cell pools, and behavioral phenotypes similar to those of ADHD-like hyperactivity. These zebrafish demonstrated compromised myelination, synaptic anomalies, and neurotransmitter imbalances. The axons of the dhcr7 −/− zebrafish showed increased lysosomes and attenuated autophagy, suggesting that autophagy-related neuronal homeostasis is disrupted. • DHCR7 mutations lead to SLOS due to disrupted cholesterol homeostasis. • Cholesterol decreases, whereas 7-DHC increases in dhcr7 −/− zebrafish. • Dhcr7 −/− zebrafish show microcephaly, synaptic defects, and ADHD-like hyperactivity. • DHCR7 deficiency disrupts autophagy-related neuronal homeostasis in axons. [ABSTRACT FROM AUTHOR]

Abstract: Previously, we found that bis(allixinato)oxovanadium(IV) (VO(alx)2) exhibits a potent hypoglycemic activity in type 1-like diabetic mice. Since the enhancement of insulin sensitivity is involved in one of the mechanisms by which vanadium exerts its anti-diabetic effects, VO(alx)2 was further tested in type 2 diabetes with low insulin sensitivity. The effect of oral administration of VO(alx)2 was examined in obesity-linked type 2 diabetic KKAy mice. Treatment of VO(alx)2 for 4 weeks normalized hyperglycemia, glucose intolerance, hyperinsulinemia, hypercholesterolemia and hypertension in KKAy mice; however, it had no effect on hypoadiponectinemia. VO(alx)2 also improved hyperleptinemia, following attenuation of obesity in KKAy mice. This is the first example in which a vanadium compound improved leptin resistance in type 2 diabetes by oral administration. On the basis of these results, VO(alx)2 is proposed to enhance not only insulin sensitivity but also leptin sensitivity, which in turn improves diabetes, obesity and hypertension in an obesity-linked type 2 diabetic animal. [Copyright &y& Elsevier]