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1.
Figure 6

Figure 6. Human obesity is associated with decreased expression of RNA processing genes and can influence metabolic phenotypes. From: Expression of the Splicing Factor Gene SFRS10 is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis.

Reduced expression of the splicing factor SFRS10 alters splicing of LPIN1, leading to dysregulation of lipogenic pathways and contributing to hypertriglyceridemia. Other alterations in RNA processing in human obesity should be identified (dashed arrows).

Jussi Pihlajamäki, et al. Cell Metab. ;14(2):208-218.
2.
Figure 5

Figure 5. Increased expression of lipogenic genes and lipogenesis in response to SFRS10 siRNA is reversed with LPIN1β knockdown. From: Expression of the Splicing Factor Gene SFRS10 is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis.

HepG2 cells were transfected with the indicated siRNA and analyzed 4 days later. (A) mRNA levels were determined by RT-PCR. (B) Lipogenesis, (C) TAG accumulation and (D) lysophosphatidic acid levels were measured as in Methods. Data are mean±SEM of triplicates, representative of 3 independent experiments. *, p<0.05 vs. SCR siRNA. #, p<0.05 vs. SFRS10 siRNA. See Fig S5.

Jussi Pihlajamäki, et al. Cell Metab. ;14(2):208-218.
3.
Figure 3

Figure 3. Sfrs10 heterozygous (Het) mice show increased lipogenic gene expression and hypertriglyceridemia. From: Expression of the Splicing Factor Gene SFRS10 is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis.

Wild-type (WT) and Sfrs10 Het mice were fasted for 16 hours and then refed for 10 hours before sacrifice. (A) Liver Sfrs10 mRNA and protein levels were determined by RT-PCR and Western blot. (B) Liver mRNA was quantified by RT-PCR. (C) Liver TAG and (D) plasma TAG were measured as in Methods. (E) Plasma lipoprotein profile was determined by FPLC. (F) VLDL secretion was calculated by quantifying plasma TAG after Tyloxapol administration. Data are mean±SEM of at least 5 mice/group and are representative of 2 independent cohorts. *, p<0.05 vs. WT. See Fig S4.

Jussi Pihlajamäki, et al. Cell Metab. ;14(2):208-218.
4.
Figure 2

Figure 2. SFRS10 knockdown increases expression of lipogenic genes and leads to TAG accumulation in hepatic cells. From: Expression of the Splicing Factor Gene SFRS10 is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis.

HepG2 cells were transfected with scramble (SCR) or SFRS10 siRNA and analyzed 4 days later. (A) SFRS10 mRNA and protein levels were analyzed by RT-PCR and Western blot. (B) mRNA levels were determined by RT-PCR. (C) Lipogenesis (from 14C-acetate), (D) TAG levels, (E) TAG synthesis, and (F) fatty acid oxidation were measured as described in Methods. Data are mean±SEM of triplicates, representative of 3 independent experiments. *, p<0.05 vs. SCR siRNA. See Fig S2.

Jussi Pihlajamäki, et al. Cell Metab. ;14(2):208-218.
5.
Figure 1

Figure 1. RNA processing gene expression is downregulated in obesity. From: Expression of the Splicing Factor Gene SFRS10 is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis.

(A) Top-ranking downregulated pathways in obese humans identified through GO-based pathway analysis (MAPPFinder) of microarray data from liver and muscle. (B) Heatmap of 13 RNA processing genes with decreased gene expression in both tissues. Blue indicates lower and red higher gene expression. NGT, normal glucose tolerance; IGT, impaired glucose tolerance; T2D, type 2 diabetes. (C) Expression of RNA processing genes was determined by RT-PCR from mouse liver and muscle after 4 month of HFD (black bars) compared to chow diet (white bars). Data are mean±SEM. *, p<0.05 vs. chow (n=6). (D) Protein levels of SFRS10, SFPQ and HNRPK were measured by Western blot from liver nuclear extracts. See Fig S1.

Jussi Pihlajamäki, et al. Cell Metab. ;14(2):208-218.
6.
Figure 4

Figure 4. SFRS10 regulates LPIN1 splicing. From: Expression of the Splicing Factor Gene SFRS10 is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis.

(A) The putative binding site of SFRS10, GGAA, is highlighted in gray within alternatively spliced exon 6 sequence (Ensembl release 61) of human and mouse LPIN1. The U1 snRNA binding site at the 5’ splice site is underlined. (B) SFRS10 cotransfection increases exclusion of LPIN1 exon 6 in a minigene system (left), while SFRS10 siRNA increases inclusion (right). PCR primers are shown as arrows. (C–D) Expression of total LPIN1, LPIN1β and LPIN1α isoforms was determined (RT-PCR) in: (C) HepG2 cells after SCR (white bars) or SFRS10 siRNA (black bars), and (D) liver samples from WT (white, n=7) and Sfrs10 heterozygous (black, n=5) mice. (E–G) Expression of Lpin1β relative to Lpin1α was measured by RT-PCR in liver from: (E) HFD (black, n=6) and chow (white, n=6) mice, (F) lean (white, n=6) or obese (black, n=14) humans, and (G) Hepa1c cells after GFP (white, n=5) or SFRS10 (black, n=5) overexpression. Data are mean±SEM. *, p<0.05 vs. control. See Fig S2.

Jussi Pihlajamäki, et al. Cell Metab. ;14(2):208-218.

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