Hyperlipidemic Effects of Dietary Saturated Fats Mediated through PGC-1β Coactivation of SREBP

Lin, Jiandie D.; Yang, Ruojing; Tarr, Paul T.; Wu, Pei Hsuan; Handschin, Christoph; Li, Siming; Yang, Wenli; Pei, Liming; Uldry, Marc; Tontonoz, Peter; Newgard, Christopher B.; Spiegelman, Bruce M.

doi:10.1016/j.cell.2004.11.043

Cited by 568 publications

(523 citation statements)

References 49 publications

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“…In a similar way, it has been recently demonstrated that SFA, which induces hyperlipidemia and atherogenesis, stimulate the expression of the sterol responsive element binding protein (SREBP) (Lin et al 2005). Nevertheless, some effects of n-3 PUFA and SFA on physiological processes remain poorly defined.…”

Section: Resultsmentioning

confidence: 99%

Influence of environmental medium on membrane fatty acid composition of Reuber H35 hepatoma cells

García-Pelayo

Garcia-Peregrin

Martínez-Cayuela

2013

Frontiers in Life Science

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Cell membrane proteins are sensitive to their fatty acid environment; however, the effects of those fatty acids are not completely understood. In this work, we have optimized a model for the study of membrane protein regulation, which allows the investigation of lipid metabolism in cultured tumor cells. The membrane fatty acid composition of Reuber H35 hepatoma cells was modified by enriching phospholipids in individual fatty acids of different length and degree of saturation. Lauric, myristic, eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids were supplemented to the culture medium of cells growing in presence or absence of lipoproteins. The four fatty acids were incorporated into membrane phospholipids in a dosedependent manner. Lauric and myristic acids were actively metabolized, increasing percentages of longer and unsaturated chain fatty acids, but they did not modify the unsaturated index. As expected, EPA and DHA significantly decreased the unsaturated index. Incorporation of EPA and DHA was accompanied of a significant decrease of total monounsaturated fatty acids and an increase of total saturated fatty acids. Our results demonstrate that Reuber H35 hepatoma cells constitute a suitable model to manipulate the lipid composition of the cell membranes and perform functionality studies on the membrane proteins in response to their lipid environment.

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Section: Resultsmentioning

confidence: 99%

Influence of environmental medium on membrane fatty acid composition of Reuber H35 hepatoma cells

García-Pelayo

Garcia-Peregrin

Martínez-Cayuela

2013

Frontiers in Life Science

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“…A strong association was observed between TRIB3 mRNA and transcript levels of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1 beta (PPARGC1B, also referred to as PGC-1β, which, in contrast to PPARGC1A, has been shown to bind and directly co-activate SREBPs [11]. Despite a modest association between TRIB3 transcripts and transcripts encoding SREBP-1c, recent studies have shown that nuclear import of SREBP-1c is enhanced by endoplasmic reticulum stress, which is implicated in insulin resistance [12].…”

Section: Resultsmentioning

confidence: 99%

Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans

et al. 2010

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Aims/hypothesis The pseudokinase tribbles homologue 3 (Drosophila) (TRIB3) negatively interferes with insulinmediated phosphorylation and activation of v-akt murine thymoma viral oncogene homologue 1 (AKT1, also known as protein kinase B). Animal studies have shown that Trib3 expression was higher in the fasting state and in animal models of diabetes, promoting hyperglycaemia presumably by increasing glucose production in the liver. Less is known about the role of TRIB3 in insulin resistance in humans, although a gain-of-function mutation associated with abnormalities related to insulin resistance has been described in TRIB3. Methods We determined hepatic mRNA expression of TRIB3 and selected genes encoding enzymes, transcription factors and coactivators involved in glucose homeostasis. We also determined biochemical variables of intermediary metabolism in obese patients with varying degrees of insulin resistance. ResultsIn our study population hepatic TRIB3 mRNA expression was associated with surrogate markers of insulin resistance. TRIB3 expression was significantly increased in a subgroup with high HOMA of insulin resistance (HOMA-IR) compared with a low HOMA-IR group (p=0.0033). TRIB3 transcript levels were correlated with PEPCK (also known as PCK2) mRNA expression (p=0.0014) and mRNA expression of PPARGC1A (p=0.0020), PPARGC1B (p<0.0001), USF1 (p=0.0017), FOXO1 (p=0.0003) and SREBP-1c (also known as SREBF1; p=0.0360). Furthermore ligands of peroxisome proliferator-activated receptor α/retinoid X receptor and overexpression of its coactivator PPARGC1A as well as overexpression of SREBP-1c and its coactivator PPARGC1B increased TRIB3 promoter activity in HepG2 cells. Conclusions/interpretation We have found evidence for a role of aberrant hepatic TRIB3 transcript levels in insulin resistance in obese humans and identified potential transcriptional pathways involved in regulation of TRIB3 gene expression in the liver.

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“…It has recently been reported that a diet rich in saturated fat increased expression of the transcriptional co-activator PGC1b (Lin et al, 2005). This in turn was shown to enhance the transcriptional activity of SREBP1c.…”

Section: Regulation Of Gene Expression By Dietary Lipidsmentioning

confidence: 99%

Regulation of gene transcription by fatty acids

Salter

Tarling

2007

Animal

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Dietary fat is well recognised as an important macronutrient that has major effects on growth, development and health of all animals including humans. The amount and type of fat in the diet impacts on many aspects of metabolism including lipoprotein pathways, lipid synthesis and oxidation, adipocyte differentiation and cholesterol metabolism. It has become increasingly apparent that many of these effects may be due to direct modulation of expression of key genes through the interaction of fatty acids with certain transcription factors. Peroxisome proliferator-activated receptors (PPARs), the liver X receptors (LXRs), hepatic nuclear factor 4 (HNF-4) and sterol regulatory binding proteins (SREBPs) represent four such factors. This review focuses on emerging evidence that the activity of these transcription factors are regulated by fatty acids and the interactions between them may be responsible for many of the effects of fatty acids on metabolism and the development of chronic disease.

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Hyperlipidemic Effects of Dietary Saturated Fats Mediated through PGC-1β Coactivation of SREBP

Cited by 568 publications

References 49 publications

Influence of environmental medium on membrane fatty acid composition of Reuber H35 hepatoma cells

Influence of environmental medium on membrane fatty acid composition of Reuber H35 hepatoma cells

Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans

Regulation of gene transcription by fatty acids

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