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

Abstract

The combined prevalence of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus is 10.5% worldwide and this is constantly increasing. The pathophysiology of the diseases include disturbances of the lipid metabolism, in which acyl-CoA desaturases play a central role as they synthesize unsaturated fatty acids, thereby providing protection against lipotoxicity. The stearoyl-CoA desaturase-5 (SCD5) isoform has received little scientific attention. We aimed to investigate the SCD5 promoter and its polymorphisms in vitro, in silico and in a case-control study. The SCD5 promoter region was determined by a luciferase reporter system in HepG2, HEK293T and SK-N-FI cells and it was proved to be cell type-specific, but it was insensitive to different fatty acids. The effect of the SCD5 promoter polymorphisms rs6841081 and rs3811792 was tested in the transfected cells. The T allele of rs3811792 single nucleotide polymorphism (SNP) significantly reduced the activity of the SCD5 promoter in vitro and modified several transcription factor binding sites in silico. A statistically significant association of rs3811792 SNP with T1DM and T2DM was also found, thus supporting the medical relevance of this variation and the complexity of the molecular mechanisms in the development of metabolic disorders. In conclusion, the minor allele of rs3811792 polymorphism might contribute to the development of diabetes by influencing the SCD5 promoter activity.

Molecular Basis of Unequal Alternative Splicing of Human SCD5 and Its Alteration by Natural Genetic Variations

“…The tissue distribution of SCD1 is well characterized [ 4 ]. Similar data are also available for SCD5 , but without distinguishing its two TVs [ 2 , 5 , 6 , 7 ]. We, therefore, examined the mRNA expression of SCD1 , SCD5A and SCD5B in ten human tissues (liver, brain, pancreas, kidney, lung, small intestine, spleen, skeletal muscle, ovary and testis; Figure 2 ).…”

“…Although the characteristic gene expression of both SCD1 and SCD5 has been investigated separately in human tissues [ 2 , 4 , 5 , 6 , 7 , 33 ], no experimental data are available on the distribution of the two isoforms within a given tissue, nor have the two TVs of SCD5 been distinguished in the studies. We analyzed the mRNA expression of SCD1 , SCD5A and SCD5B in ten human tissues.…”

“…The two human isoforms show markedly different gene expression patterns. While SCD1 is mainly expressed in the major organs of lipid metabolism [ 4 ], SCD5 is highly represented in the embryonic and mature brain, pancreas and gonads instead [ 2 , 5 , 6 , 7 ]. In addition, increasing evidence suggests that SCD5 gene expression may be less dependent on lipid factors compared to other mammalian desaturases.…”

“…In addition, increasing evidence suggests that SCD5 gene expression may be less dependent on lipid factors compared to other mammalian desaturases. In contrast to SCD1 , the promoter activity of SCD5 has been shown to be insensitive to several FAs in vitro [ 6 ]. Despite the in silico identification of transcription factor (TF) binding sites constituting the PUFA response region (SREBP1, SP1, PGC1 α , NF1, NFY) in the 5′ regulatory sequence of SCD5 [ 8 , 9 ], neither diets containing various unsaturated FAs [ 10 ], changes in serum lipid levels [ 11 ], nor the presence of retinoic acid [ 12 ] affected SCD5 mRNA levels.…”

“…Despite the in silico identification of transcription factor (TF) binding sites constituting the PUFA response region (SREBP1, SP1, PGC1 α , NF1, NFY) in the 5′ regulatory sequence of SCD5 [ 8 , 9 ], neither diets containing various unsaturated FAs [ 10 ], changes in serum lipid levels [ 11 ], nor the presence of retinoic acid [ 12 ] affected SCD5 mRNA levels. However, certain promoter polymorphisms of SCD5 have been proven to significantly reduce the promoter activity in vitro, modify TF binding sites in silico and were associated to metabolic disorders [ 6 ].…”