Genetic variant of the SREBF-1 gene is significantly related to cholesterol synthesis in man

doi:10.1016/j.atherosclerosis.2005.06.007

Atherosclerosis

Volume 185, Issue 1, March 2006, Pages 206-209

https://doi.org/10.1016/j.atherosclerosis.2005.06.007 Get rights and content

Abstract

Sterol regulatory element binding proteins-1 and -2 (SREBPs) are transcription factors controlling lipid homeostasis in human cells. The G-allele carriers of the SREBF-1 gene C–G polymorphism in exon 18c and coding for glycine at the protein level (G952G) have shown to associate more frequently with obesity and type 2 diabetes than the C-allele carriers. However, the C-allele has suggested to be linked to dyslipidemia. Thus, our aim was to study effect of the SREBF-1 gene polymorphism (G952G) on sterol metabolism in man.

Ninety-five subjects with moderate hypercholesterolemia participated in this study and 14 homozygous CC carriers of the SREBF-1 (G952G) gene were found. Plasma lathosterol concentration and lathosterol-to-cholesterol ratio, markers of endogenous cholesterol synthesis, were significantly higher in CC homozygous subject compared to others. Similarly muscle cholesterol (p = 0.045) and lathosterol (p = 0.054) concentrations were elevated in the CC homozygotes supporting the view that endogenous cholesterol synthesis rate is SREBF-1 genotype-dependent.

Section snippets

Research design and methods

Ninety-five subjects aged between 26 and 69 years (80 men and 15 women) were recruited. Their average serum total cholesterol concentration was 5.7 ± 0.8 mmol/L and they had never been on lipid lowering treatment. Patients with familial hypercholesterolemia were excluded. The study protocol was accepted by the Ethics Committee of the Tampere University Hospital and Turku University Hospital. Written informed consents were obtained of all participants.

Results

In this study, women had higher plasma cholesterol (6.87 mmol/L versus 5.64 mmol/L; p = 0.000) and lathosterol (8.48 nmol/L versus 6.49 nmol/L; p = 0.02) levels than men. Age associated significantly with plasma cholesterol (r = 0.32, p = 0.001) and plasma sitosterol (r = −0.21, p = 0.047). Sterol absorption markers campesterol-to-cholesterol and sitosterol-to-cholesterol ratios were also associated with age (r = −0.30, p = 0.004; r = −0.33, p = 0.01, respectively). BMI was significantly related to plasma lathosterol (

Discussion

This study demonstrated that the SREBF-1 gene G952G variant is affecting sterol metabolism in man. Plasma lathosterol-to-cholesterol ratios are used as markers of cholesterol synthesis [11], [12], [13]. The present results indicate that the CC homozycotes of the SREBF-1 gene G952G variant have a higher cholesterol synthesis rate than GG or GC carriers. This observation was further supported by results obtained in muscle biopsy analyses. Muscle cholesterol concentrations were significantly

Acknowledgements

We are indebted to the personnel of the out patient clinic and laboratory of the Tampere University Hospital and Department of Clinical Pharmacology, University of Helsinki, for their valuable help during the study. We wish to thank also all the volunteers who participated in this study.

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Short-chain fatty acids are important nutrients that regulate milk fat synthesis. They regulate milk synthesis via the sterol regulatory element binding protein 1 (SREBP1) pathway; however, the details are still unknown. Here, the regulation and mechanism of sodium acetate (SA) in milk fat synthesis in bovine mammary epithelial cells (BMECs) were assessed. BMECs were treated with SA supplementation (SA+) or without SA supplementation (SA-), and milk fat synthesis and activation of the SREBP1 pathway were increased (P = 0.0045; P = 0.0042) by SA+ and decreased (P = 0.0068; P = 0.0031) by SA-, respectively. Overexpression or inhibition of SREBP1 demonstrated that SA promoted milk fat synthesis (P = 0.0045) via the SREBP1 pathway. Overexpression or inhibition of TATA element modulatory factor 1 (TMF1) demonstrated that TMF1 suppressed activation of the SREBP1 pathway (P = 0.0001) and milk fat synthesis (P = 0.0022) activated by SA+. Overexpression or inhibition of TMF1 and SREBP1 showed that TMF1 suppressed milk fat synthesis (P = 0.0073) through the SREBP1 pathway. Coimmunoprecipitation analysis revealed that TMF1 interacted with SREBP1 in the cytoplasm and suppressed the nuclear localization of SREBP1 (P = 0.0066). The absence or presence of SA demonstrated that SA inhibited the expression of TMF1 (P = 0.0002) and the interaction between TMF1 and SREBP1 (P = 0.0001). Collectively, our research suggested that TMF1 was a new negative regulator of milk fat synthesis. In BMECs, SA promoted the SREBP1 pathway and milk fat synthesis by suppressing TMF1. This study enhances the current understanding of the regulation of milk fat synthesis and provides new scientific data for the regulation of milk fat synthesis.
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We hypothesize that the magnitude of ABCA1 upregulation (~5-fold higher than the control) upon TPT exposure (Fig. 7A), which was half to that of TBT (~10-fold), did not surpass a threshold to result in intracellular cholesterol loss. Alternatively, the upregulation of LDLR that aids in cholesterol internalization (Go and Mani, 2012; Guillemot et al., 2016) and SREBF1 that increases intracellular cholesterol biosynthesis (Horton et al., 2002; Laaksonen et al., 2006) may have contributed to the stabilization of intracellular cholesterol levels despite higher cholesterol efflux through ABCA1 upregulation. Since both, LDLR and SREBF1 can be stimulated by LXR activation (Xu et al., 2019; van Loon et al., 2020), our findings suggest that their upregulation is likely driven by TPT's binding on LXR.
Organotins, a chemical family with over 30 congeners to which humans are directly exposed to through food consumption, are a chemical class widely used as stabilizers in polyvinyl chloride, and biocides in antifouling products. Aside from tributyltin (TBT), toxicological information on other organotin congeners, such as triphenyltin (TPT), remains scarce. Our previous work has demonstrated that TBT can interfere with cholesterol trafficking in steroidogenic cells. Given their structural similarities, we hypothesized that TPT, similar to TBT, disrupts intracellular cholesterol transport and impairs steroidogenesis in ovarian theca cells. To test this, human and ovine primary ovarian theca cells were isolated, purified and exposed to TPT at environmentally relevant doses (1 or 10 ng/ml) in pre-luteinized (48 h exposure) or luteinizing cells (72 h exposure). Intracellular cholesterol levels, progesterone, and testosterone secretion and gene expression of nuclear receptors, cholesterol transporters, and steroidogenic enzymes were evaluated. In ovine cells, TPT upregulated StAR, ABCA1, and SREBF1 mRNA and ABCA1 protein in both pre-luteinized and luteinized stages. TPT did not alter intracellular cholesterol or testosterone synthesis, but upregulated progesterone production. Inhibitor and shRNA knockdown approaches were then used to evaluate the role of retinoid X receptor (RXR) and liver X receptor (LXR) on TPT's effects. TPT upregulated ABCA1 and StAR expression was blocked by both LXR and RXR antagonists. TPT's effect on ABCA1 expression was reduced in LXRβ and RXRβ knockdown theca cells. Similar findings were obtained with primary human theca cells. No synergistic effect of TBT and TPT was observed. In conclusion, at an environmentally relevant dose, TPT upregulates theca cell cholesterol transporter ABCA1 expression via RXR and LXR pathways. Similar effects of TPT on human and sheep theca cells supports its conserved mechanism across mammalian theca cells.
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PRISMA guidelines were followed [8]. Data of 21 studies could be used to examine cross-sectional relationships between gene polymorphisms with plasma or serum non-cholesterol sterol levels as markers for intestinal cholesterol absorption [9–29]. Characteristics of these 21 studies are summarized in Supplementary Table 1.
Intestinal cholesterol absorption varies widely between individuals, which may translate into differences in responsiveness to cholesterol-lowering drugs or diets. Therefore, understanding the importance of genetic variation on cholesterol absorption rates and the complex intestinal cholesterol network is important. Based on a systematic review, genetic variants in seven genes (ABCG5, ABCG8, ABO, APOE, MTTP, NPC1L1, and LDLR) were identified that were associated with intestinal cholesterol absorption. No clear associations were found for variants in APOA4, APOB, CETP, CYP7A1, HMGCR, SCARB1, SLCO1B1, and SREBF1. The seven genes were used to construct an intestinal cholesterol absorption network. Finally, a network with fifteen additional genes (APOA1, APOA4, APOB, APOC2, APOC3, CETP, HSPG2, LCAT, LDLRAP1, LIPC, LRP1, OLR1, P4HB, SAR1B, and SDC1) was generated. The constructed network shows that cholesterol absorption is complex. Further studies are needed to validate and improve this network, which may ultimately lead to a better understanding of the wide inter-individual variability in intestinal cholesterol absorption and the development of personalized interventions.
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Maintenance of lipid homeostasis is crucial for cells in response to lipid requirements or surplus. The SREBP transcription factors play essential roles in regulating lipid metabolism and are associated with many metabolic diseases. However, SREBP regulation of lipid metabolism is still not completely understood. Here, we showed that reduction of SBP-1, the only homolog of SREBPs in Caenorhabditis elegans, surprisingly led to a high level of zinc. On the contrary, zinc reduction by mutation of sur-7, encoding a member of the cation diffusion facilitator (CDF) family, restored the fat accumulation and fatty acid profile of the sbp-1(ep79) mutant. Zinc reduction resulted in iron overload, which thereby directly activated the conversion activity of stearoyl-CoA desaturase (SCD), a main target of SREBP, to promote lipid biosynthesis and accumulation. However, zinc reduction reversely repressed SBP-1 nuclear translocation and further downregulated the transcription expression of SCD for compensation. Collectively, we revealed zinc-mediated regulation of the SREBP-SCD axis in lipid metabolism, distinct from the negative regulation of SREBP-1 or SREBP-2 by phosphatidylcholine or cholesterol, respectively, thereby providing novel insights into the regulation of lipid homeostasis.
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SREBF-1c is a critical regulator of fatty acid biosynthesis in lactating mammary epithelium [16]. Studies of the genetic association have shown that the SREBF gene polymorphisms are closely related to obesity, T2DM, cardiovascular diseases, energy homeostasis, and so on [11,17–20]. In addition, previous reports have identified 19 polymorphisms (SNP1 through SNP19) in SREBF-1 gene among different specific ethnic groups [11].
A sterol regulatory element-binding protein (SREBF-1) transcription factor is a major regulator of lipid metabolism, carbohydrate, and plays a key role in energy homeostasis. The 54(G/C) polymorphism of SREBF-1 gene was reported that it is related with metabolic diseases including obesity, type 2 diabetes, and dyslipidemia. Among these, polycystic ovary syndrome (PCOS) is known as a common metabolic-endocrine disorder of women in reproductive ages.
Here, we performed a comparative study of 54(G/C) polymorphism of SREBF-1 gene with PCOS. The 54(G/C) polymorphism of SREBF-1 gene was analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) of total 286 PCOS patients and 149 matched controls of healthy women. Statistical analysis was performed using HapAnalyzer. A p-value under 0.05 was considered statistically significant.
There was a strong association between the 54(G/C) polymorphism of SREBF-1 gene and PCOS (OR: 0.65, 95% CI: 0.46–0.90, p: 0.0129). The genotype and allelic frequencies were in Hardy–Weinberg equilibrium (HWE).
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Standardized genotyping and DNA handling methods minimized potential for differential genotyping error. We used a comprehensive haplotype-based approach, in contrast to previous studies focused on single SNPs35,38,65,66 that may miss nearby regions in LD within the gene that include variants associated with the phenotype. Potential limitations should also be considered.
Previous studies observed the surprising finding that saturated fat was inversely associated with atherosclerosis progression in postmenopausal women, whereas polyunsaturated fat (PUFA) and carbohydrates were positively associated. Whether certain genes modify the association of diet with atherosclerotic progression is unknown.
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Genetic variant of the SREBF-1 gene is significantly related to cholesterol synthesis in man

Abstract

Section snippets

Research design and methods

Results

Discussion

Acknowledgements

J Lipid Res

Atherosclerosis

Atherosclerosis

Atherosclerosis

J Lipid Res

J Lipid Res

J Lipid Res