Expression of the Splicing Factor Gene SFRS10 Is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis

Abstract

SUMMARY Alternative mRNA splicing provides transcript diversity and may contribute to human disease. We demonstrate that expression of several genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. We evaluated a representative splicing factor, SFRS10, down-regulated in both obese human liver and muscle and in high fat-fed mice, and determined metabolic impact of reduced expression. SFRS10-specific siRNA induces lipogenesis and lipid accumulation in hepatocytes. Moreover, Sfrs10 heterozygous mice have increased hepatic lipogenic gene expression, VLDL secretion, and plasma triglycerides. We demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10; reduced SFRS10 favors the lipogenic β isoform of LPIN1. Importantly, LPIN1β-specific siRNA abolished lipogenic effects of decreased SFRS10 expression. Together, our results indicate that reduced expression of SFRS10, as observed in tissues from obese humans, alters LPIN1 splicing, induces lipogenesis, and therefore contributes to metabolic phenotypes associated with obesity.

Adipose tissue INSR splicing in humans associates with fasting insulin level and is regulated by weight loss

“…First, lower insulin levels in relation to INSR-B may reflect better peripheral insulin sensitivity as expected for this isoform. However, an increase in INSR-B in response to weight loss could also be secondary to lower insulin levels, as insulin is a known regulator of splicing factor activity through phosphorylation [10] and because hyperinsulinaemia associates with lower expression of splicing factors [3]. We found a correlation between INSR splicing and expression of HNRNPA1 , SF3A1 and SFRS7 in the KOBS study (ESM Table 4).…”

“…We have previously shown that expression of several splicing factors is reduced in liver and skeletal muscle of obese individuals [3]. In addition, we have shown that the splicing of TCF7L2 is regulated by weight loss in adipose tissue and liver [4].…”

“…Expression of HNRNPA1, SF3A1, SFRS7 and SFRS10 has been shown to be lower in the skeletal muscle and liver of obese individuals compared with lean individuals [3]. Therefore, we analysed the effect of weight loss on the adipose tissue expression of these genes and the association with INSR splicing.…”

Transformer 2β homolog (Drosophila) (TRA2B) Regulates Protein Kinase C δI (PKCδI) Splice Variant Expression during 3T3L1 Preadipocyte Cell Cycle

“…Regulation of alternative splicing by TRA2B is shown in several systems including LIPN1 in liver (28), splicing of myosin phosphatase targeting subunit 1 in smooth muscle (29), splicing of Tau in neurons (30) and BRCA1 gene (31). TRA2B is also shown to be involved in mouse embryogenesis and spermatogenesis as well as in meiosis in male germ cells (32).…”

MicroRNAs Responsible for Inflammation in Obesity

“…Transcriptomic alterations were treated as separate data sets to account for possible differences in transcriptional alterations observed in these tissue samples [39][40][41][42][43][44][45][46]. A data overview is depicted in Table 2.…”