Yates, C. R. | bioRxiv Science

bioRxiv2021

MSM and sesame seed oil improve hyperlipidemia and PUFA metabolism in the db/db mouse

BackgroundAn estimated 463 million people worldwide suffer from diabetes, and that number is projected to rise significantly to 700 million by 2045. One of the hallmarks of type 2 diabetes and metabolic syndrome is alterations in the lipid profile and polyunsaturated fatty acid metabolism. ObjectiveThe objective of this study was to identify lipid alterations in leptin receptor deficient db/db mice, a type 2 diabetes model, to establish a baseline biological signature for the evaluation of natural products with purported lipid-altering activity. MethodsSix-week old male db/db mice (n = 10/group) were randomized to the following groups: 1) diabetic control with no treatment, 2) methylsulfonylmethane (MSM) treatment (3.81 {+/-} 0.33 g/kg), 3) sesame seed oil (SSO) treatment (23.54 {+/-} 2.91 mg/kg), and 4) MSM and SSO combination treatment, receiving the same dosages of MSM and SSO as the single treatment groups. Eight-week old male C57BL6/J mice (n=10) were used as a non-diabetic control group. ResultsSerum triglycerides and total cholesterol were significantly increased in the db/db model compared to nondiabetic control, mimicking diabetes in people. High-density lipoprotein (HDL) was significantly increased in all db/db treatment groups, with the most significant effect in the MSM and SSO combination group, with a corresponding decrease in non-HDL cholesterol. Serum total polyunsaturated fatty acid (PUFA) levels were significantly reduced in diabetic mice compared with control mice. In contrast, treatment with SSO alone reversed this effect such that fed mice exhibited serum PUFA levels comparable to control mice. ConclusionsTreatment of db/db mice with MSM and SSO improved commonly measured clinical parameters in serum lipid panels. The combination of MSM and SSO treatments effects on HDL and non-HDL cholesterol and fatty acid metabolism could lead to improved clinical outcomes in diabetics, such as reduced incidence of atherosclerosis and hepatic steatosis.

pharmacology and toxicology↗

bioRxiv2020

Sequential dynamics of Stearoyl-CoA Desaturase-1 (SCD1) /ligand binding and unbinding mechanism: A computational study

Stearoyl-CoA desaturase-1 (SCD1 or delta-9 desaturase, D9D) is a key metabolic protein that modulates cellular inflammation and stress, but overactivity of SCD1 is associated with diseases including cancer and metabolic syndrome. This transmembrane endoplasmic reticulum protein converts saturated fatty acids into monounsaturated fatty acids, primarily stearoyl-CoA into oleoyl-CoA, which are critical products for energy metabolism and membrane composition. The present computational molecular dynamics study characterizes the molecular dynamics of SCD1 with substrate, product, and as apoprotein. The modeling of SCD1:fatty acid interactions suggests that 1) SCD1:CoA moiety interactions open the substrate binding tunnel, 2) SCD1 stabilizes a substrate conformation favorable for desaturation, and 3) SCD1:product interactions result in an opening of the tunnel, possibly allowing product exit into the surrounding membrane. Together, these results describe a highly dynamic series of SCD1 conformations resulting from the enzyme:cofactor:substrate interplay that inform drug-discovery efforts.

biochemistry↗