Molecular Mechanisms Underlying the Elevated Expression of a Potentially Type 2 Diabetes Mellitus Associated SCD1 Variant

Abstract

Disturbances in lipid metabolism related to excessive food intake and sedentary lifestyle are among major risk of various metabolic disorders. Stearoyl-CoA desaturase-1 (SCD1) has an essential role in these diseases, as it catalyzes the synthesis of unsaturated fatty acids, both supplying for fat storage and contributing to cellular defense against saturated fatty acid toxicity. Recent studies show that increased activity or over-expression of SCD1 is one of the contributing factors for type 2 diabetes mellitus (T2DM). We aimed to investigate the impact of the common missense rs2234970 (M224L) polymorphism on SCD1 function in transfected cells. We found a higher expression of the minor Leu224 variant, which can be attributed to a combination of mRNA and protein stabilization. The latter was further enhanced by various fatty acids. The increased level of Leu224 variant resulted in an elevated unsaturated: saturated fatty acid ratio, due to higher oleate and palmitoleate contents. Accumulation of Leu224 variant was found in a T2DM patient group, however, the difference was statistically not significant. In conclusion, the minor variant of rs2234970 polymorphism might contribute to the development of obesity-related metabolic disorders, including T2DM, through an increased intracellular level of SCD1.

A Single Nucleotide Polymorphism (rs3811792) Affecting Human SCD5 Promoter Activity Is Associated with Diabetes Mellitus

“…It is known that the promoter activity of SCD1 is influenced positively by the SFAs, and it is negatively influenced by the MUFAs and PUFAs [ 16 , 17 , 18 , 19 , 20 , 21 , 24 ]; in addition, oleate also enhances the intracellular degradation of the SCD1 protein [ 29 , 43 ]. Furthermore, a common missense polymorphism in the SCD1 gene can stabilize the protein in an FA-dependent manner [ 23 ]. Although the two desaturases catalyze the same reaction, increasing evidence suggests that SCD5 may be less sensitive to the regulation by lipid factors in comparison to SCD1.…”

“…The present work is the first to functionally examine the two promoter SNPs of human SCD5 , and it revealed that the T allele of rs3811792 reduces the SCD5 promoter activity in the kidney-derived and neuronal cell lines. Interestingly, not only the SCD5, but also the human SCD1 polymorphisms have been quite neglected, and only a few variants have been characterized so far, and there is no promoter SNP among them, instead there is only the stabilizing effect of a missense variant [ 23 ] and the microRNA binding site-modifying role of a 3′ untranslated region (3′ UTR) polymorphism [ 44 ] have been described.…”

“…Numerous studies have demonstrated the inevitable importance of stearoyl-CoA desaturase-1 (SCD1) in the metabolic and signaling pathways, making its role unquestionable in several prevalent human diseases, including obesity, diabetes, fatty liver, and cardiovascular diseases [ 11 , 12 , 13 , 14 , 15 ]. Much is known about the lipid-sensitive expression [ 16 , 17 , 18 , 19 , 20 , 21 ], rapid protein degradation [ 22 , 23 ], and complex transcriptional regulation [ 24 ] of SCD1.…”

New Advances in Diabetes Genetics

“…The molecular diagnosis is fundamental in rare forms to choose the appropriate treatment, to reduce the risk of consequences, and for genetic counselling. This Special Issue contains two reviews [ 1 , 2 ], three original papers [ 3 , 4 , 5 ], and one case report [ 6 ] that address genetic issues in diabetes mellitus.…”

“…Several loci are involved in type 2 diabetes mechanisms. Tibori et al [ 4 ] focused their attention on the effect of the missense rs2234970 single-nucleotide polymorphism (SNP) on stearoyl-CoA desaturase-1 activity. This enzyme plays an important role in the synthesis of unsaturated fatty acids.…”