Docosahexaneoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways

Botolin, Daniela; Wang, Yun; Christian, Barbara; Jump, Donald Β.

doi:10.1194/jlr.m500365-jlr200

Cited by 148 publications

(142 citation statements)

References 42 publications

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“…We found no effect of p38 MAPK inhibitors on L-PK gene expression (not shown). 22:6,n-3, but not 20:5,n-3, induces ERK phosphorylation (51). We speculate that 20:5,n-3 regulates other signal transduction pathways that impact MLX and ChREBP nuclear abundance and HNF-4␣ interaction with the L-PK promoter.…”

Section: Discussionmentioning

confidence: 97%

“…n-3 PUFA effects on PPAR␣-regulated transcripts and mRNA SREBP-1c closely parallel changes in intracellular nonesterified 20:5,n-3 (45, 51). 20:5,n-3 is a minor fatty acid in both nonesterified and esterified lipid fractions of liver and hepatocytes (51). At any time point examined in this study, Ͼ95% of all intracellular 20:5,n-3 is esterified.…”

Section: Discussionmentioning

confidence: 98%

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Regulation of Rat Hepatic L-Pyruvate Kinase Promoter Composition and Activity by Glucose, n-3 Polyunsaturated Fatty Acids, and Peroxisome Proliferator-activated Receptor-α Agonist

Christian

Jump

2006

Journal of Biological Chemistry

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Carbohydrate regulatory element-binding protein (ChREBP), MAX-like factor X (MLX), and hepatic nuclear factor-4␣ (HNF-4␣) are key transcription factors involved in the glucose-mediated induction of hepatic L-type pyruvate kinase (L-PK) gene transcription. n-3 polyunsaturated fatty acids (PUFA) and WY14643 (peroxisome proliferatoractivated receptor ␣ (PPAR␣) agonist) interfere with glucose-stimulated L-PK gene transcription in vivo and in rat primary hepatocytes. Feeding rats a diet containing n-3 PUFA or WY14643 suppressed hepatic mRNA L-PK but did not suppress hepatic ChREBP or HNF-4␣ nuclear abundance. Hepatic MLX nuclear abundance, however, was suppressed by n-3 PUFA but not WY14643. In rat primary hepatocytes, glucose-stimulated accumulation of mRNA LPK and L-PK promoter activity correlated with increased ChREBP nuclear abundance. This treatment also increased L-PK promoter occupancy by RNA polymerase II (RNA pol II), acetylated histone H3 (Ac-H3), and acetylated histone H4 (Ac-H4) but did not significantly impact L-PK promoter occupancy by ChREBP or HNF-4␣. Inhibition of L-PK promoter activity by n-3 PUFA correlated with suppressed RNA pol II, Ac-H3, and Ac-H4 occupancy on the L-PK promoter. Although n-3 PUFA transiently suppressed ChREBP and MLX nuclear abundance, this treatment did not impact ChREBP-LPK promoter interaction. HNF4␣-LPK promoter interaction was transiently suppressed by n-3 PUFA. Inhibition of L-PK promoter activity by WY14643 correlated with a transient decline in ChREBP nuclear abundance and decreased Ac-H4 interaction with the L-PK promoter. WY14643, however, had no impact on MLX nuclear abundance or HNF4␣-LPK promoter interaction. Although overexpressed ChREBP or HNF-4␣ did not relieve n-3 PUFA suppression of L-PK gene expression, overexpressed MLX fully abrogated n-3 PUFA suppression of L-PK promoter activity and mRNA L-PK abundance. Overexpressed ChREBP, but not MLX, relieved the WY14643 inhibition of L-PK. In conclusion, n-3 PUFA and WY14643/PPAR␣ target different transcription factors to control L-PK gene transcription. MLX, the heterodimer partner for ChREBP, has emerged as a novel target for n-3 PUFA regulation.The glycolytic enzyme, liver-type pyruvate kinase (L-PK), 2 plays a key role in hepatic glucose and lipid metabolism (1). Phosphorylation and allosteric factors acutely regulate L-PK enzyme activity, whereas hormones and nutrients chronically control the abundance of L-PK protein by regulating L-PK gene transcription. Excess glucose consumption induces glycolysis, L-PK activity, de novo lipogenesis, and lipid storage, whereas n-3 polyunsaturated fatty acids (n-3 PUFA) inhibit these metabolic events (2, 3). L-PK gene transcription is induced by insulin-stimulated glucose metabolism (4) and inhibited by n-3 PUFA and activators of PPAR␣ (WY14643), protein kinase A, and AMP kinase (AMPK) (5-8).Key cis-regulatory elements controlling L-PK gene transcription are located between Ϫ197 and Ϫ125 bp upstream of the transcription start site (Fig. 1). Two basic helix-loop-helix transcri...

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 98%

Regulation of Rat Hepatic L-Pyruvate Kinase Promoter Composition and Activity by Glucose, n-3 Polyunsaturated Fatty Acids, and Peroxisome Proliferator-activated Receptor-α Agonist

Christian

Jump

2006

Journal of Biological Chemistry

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“…Several candidate molecules involved in the regulation of lipid synthesis in rodents have not been investigated in ruminants. These include: (i) protein kinase B (PKB/Akt) with evidence that Akt1-mediated inhibition of GSK3 enhances the stability of SREBP1 since phosphorylation of SREBP1 by GSK3 enhances the ubiquitination and degradation of SREBP in the nucleus (Anderson et al, 2007); (ii) extracellular signal-related kinase (Erk) based on observations that DHA suppresses the expression of SREBP1 in hepatocytes, changes that are mediated via Erk-dependent and 26S proteasome pathways (Botolin et al, 2006); and (iii) endoplasmic reticulum stress-regulated kinase (PERK) based on data in knock out mice models indicating that the PERK deletion in murine mammary epithelium inhibits SREBP1 activation and the sustained induction of lipogenic enzymes (Bobrovnikova-Marjon et al, 2008). Examination of alterations in the expression of these genes should provide further insight into events upstream of SREBP1 mediated regulation of lipogenic gene expression.…”

Section: Future Perspectivesmentioning

confidence: 99%

Role of trans fatty acids in the nutritional regulation of mammary lipogenesis in ruminants

Shingfield

Bernard

Leroux

et al. 2010

Animal

333

427

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Fat is an important constituent contributing to the organoleptic, processing and physical properties of ruminant milk. Understanding the regulation of milk fat synthesis is central to the development of nutritional strategies to enhance the nutritional value of milk, decrease milk energy secretion and improve the energy balance of lactating ruminants. Nutrition is the major environmental factor regulating the concentration and composition of fat in ruminant milk. Feeding low-fibre/high-starch diets and/or lipid supplements rich in polyunsaturated fatty acids induce milk fat depression (MFD) in the bovine, typically increase milk fat secretion in the caprine, whereas limited data in sheep suggest that the responses are more similar to the goat than the cow. Following the observation that reductions in milk fat synthesis during diet-induced MFD are associated with increases in the concentration of specific trans fatty acids in milk, the biohydrogenation theory of MFD was proposed, which attributes the causal mechanism to altered ruminal lipid metabolism leading to increased formation of specific biohydrogenation intermediates that exert anti-lipogenic effects. Trans-10, cis-12 conjugated linoleic acid (CLA) is the only biohydrogenation intermediate to have been infused at the abomasum over a range of experimental doses (1.25 to 14.0 g/day) and shown unequivocally to inhibit milk fat synthesis in ruminants. However, increases in ruminal trans-10, cis-12 CLA formation do not explain entirely diet-induced MFD, suggesting that other biohydrogenation intermediates and/or other mechanisms may also be involved. Experiments involving abomasal infusions (g/day) in lactating cows have provided evidence that cis-10, trans-12 CLA (1.2), trans-9, cis-11 CLA (5.0) and trans-10 18:1 (92.1) may also exert anti-lipogenic effects. Use of molecular-based approaches have demonstrated that mammary abundance of transcripts encoding for key lipogenic genes are reduced during MFD in the bovine, changes that are accompanied by decrease in sterol response element binding protein 1 (SREBP1) and alterations in the expression of genes related to the SREBP1 pathway. Recent studies indicate that transcription of one or more adipogenic genes is increased in subcutaneous adipose tissue in cows during acute or chronic MFD. Feeding diets of similar composition do not induce MFD or substantially alter mammary lipogenic gene expression in the goat. The available data suggests that variation in mammary fatty acid secretion and lipogenic responses to changes in diet composition between ruminants reflect inherent interspecies differences in ruminal lipid metabolism and mammary specific regulation of cellular processes and key lipogenic enzymes involved in the synthesis of milk fat triacylglycerides.Keywords: milk fat, trans fatty acids, gene expression, lipogenesis, ruminants ImplicationsUnderstanding the regulation of milk fat synthesis is central to the development of nutritional strategies to enhance the nutritional value of milk, decrease milk-energ...

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“…Secondly, nSREBP1 is targeted to proteosomal degradation by GSK3b-dependent phosphorylation, and Akt1 may increase nSREBP1 abundance by inactivating GSK3b (Rudolph et al, 2007;Jump et al, 2008). Botolin et al (2006) reported that n-3 PUFA decreased insulin-stimulated activation of Akt1 and increased proteasome degradation of nSREBP1, although a constituently active Akt1 did not overcome this effect. In addition, long-chain PUFA induced GSK3b phosphorylation (Jump et al, 2008).…”

Section: Sterol Response Element-binding Protein-1mentioning

confidence: 99%

Recent advances in the regulation of milk fat synthesis

Harvatine

Boisclair

Bauman

2009

Animal

266

272

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In addition to its economic value, milk fat is responsible for many of milk's characteristics and can be markedly affected by diet. Diet-induced milk fat depression (MFD) was first described over a century ago and remains a common problem observed under both intensive and extensive management. The biohydrogenation theory established that MFD is caused by an inhibition of mammary synthesis of milk fat by specific fatty acids (FA) produced as intermediates in ruminal biohydrogenation. During MFD, lipogenic capacity and transcription of key lipid synthesis genes in the mammary gland are down-regulated in a coordinated manner. Our investigations have established that expressions of sterol response element-binding protein 1 (SREBP1) and SREBP-activation proteins are down-regulated during MFD. Importantly, key lipogenic enzymes are transcriptionally regulated via SREBP1. Collectively, these results provide strong evidence for SREBP1 as a central signaling pathway in the regulation of mammary FA synthesis. Spot 14 is also down-regulated during MFD, consistent with a lipogenic role for this novel nuclear protein. In addition, SREBP1c and Spot 14 knock-out mice exhibit reduced milk fat similar to the magnitude and pattern of MFD in the cow. Application of molecular biology approaches has provided the latest chapter in the regulation of milk fat synthesis and is reviewed along with a brief background in nutritional regulation of milk fat synthesis in ruminants.

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Docosahexaneoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways

Cited by 148 publications

References 42 publications

Regulation of Rat Hepatic L-Pyruvate Kinase Promoter Composition and Activity by Glucose, n-3 Polyunsaturated Fatty Acids, and Peroxisome Proliferator-activated Receptor-α Agonist

Regulation of Rat Hepatic L-Pyruvate Kinase Promoter Composition and Activity by Glucose, n-3 Polyunsaturated Fatty Acids, and Peroxisome Proliferator-activated Receptor-α Agonist

Role of trans fatty acids in the nutritional regulation of mammary lipogenesis in ruminants

Recent advances in the regulation of milk fat synthesis

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