The Spot 14 Protein Is Required for de Novo Lipid Synthesis in the Lactating Mammary Gland

Zhu, Qi; Anderson, Grant W.; Mucha, Gregory T.; Parks, Elizabeth J.; Metkowski, Jennifer K.; Mariash, Cary N.

doi:10.1210/en.2005-0204

Cited by 85 publications

(84 citation statements)

References 37 publications

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“…S14 is also regulated by SREBPs in a manner similar to MIG12 (20) and knockout mice have reduced fatty acid synthesis in mammary glands (26). Recombinant S14 was also tested in vitro and no change in ACC1 or ACC2 activity was found (Fig.…”

Section: Discussionmentioning

confidence: 95%

Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis

Kim

Moon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

124

137

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Acetyl-CoA carboxylase (ACC), the first committed enzyme in fatty acid (FA) synthesis, is regulated by phosphorylation/dephosphorylation, transcription, and an unusual mechanism of protein polymerization. Polymerization of ACC increases enzymatic activity and is induced in vitro by supraphysiological concentrations of citrate (>5 mM). Here, we show that MIG12, a 22 kDa cytosolic protein of previously unknown function, binds to ACC and lowers the threshold for citrate activation into the physiological range (<1 mM). In vitro, recombinant MIG12 induced polymerization of ACC (as determined by nondenaturing gels, FPLC, and electron microscopy) and increased ACC activity by >50-fold in the presence of 1 mM citrate. In vivo, overexpression of MIG12 in liver induced ACC polymerization, increased FA synthesis, and produced triglyceride accumulation and fatty liver. Thus, in addition to its regulation by phosphorylation and transcription, ACC is regulated at a tertiary level by MIG12, which facilitates ACC polymerization and enhances enzymatic activity.lipogenesis | SREBPs | steatosis F atty acids (FAs) are the essential components of phospholipids and provide the most important energy depot for the body in the form of triglycerides (TG). Newly synthesized FAs also serve as signaling molecules and modulators of transcription factor activity (1-3). Excess accumulation of FAs in tissues contributes to the pathogenesis of many common diseases, including insulin resistance, nonalcoholic fatty liver disease, diabetes, and cancer (4, 5). Given the central role of FAs in these diseases, the enzymes of FA biosynthesis are potential therapeutic targets.The first committed step in FA biosynthesis is carried out by acetyl-CoA carboxylase (ACC). ACC1 was isolated and characterized by Wakil et al. (6) and functions to carboxylate acetyl-CoA to form malonyl-CoA. Subsequently, a second ACC isoform, ACC2, was identified in mammals that is encoded by a separate gene but carries out the same enzymatic reaction (7,8).ACCs are members of a larger family of carboxylases that require biotin and ATP and use bicarbonate as a carbon donor. The malonyl-CoA produced by ACC can be used by FA synthase (FAS) for the sequential 2-carbon elongation reactions that generate palmitic acid (C16:0) in the cytosol. While both ACC1 and ACC2 produce malonyl-CoA, ACC1 is predominantly cytosolic and generates malonyl-CoA that is used by FAS to synthesize palmitic acid. ACC2 is associated with the mitochondrial membrane (9) and produces malonyl-CoA that serves to allosterically inhibit carnitine palmitoyl transferase I, the protein responsible for transport of long chain FAs into mitochondria for β-oxidation (10).Regulation of ACC1 and ACC2 occurs at multiple levels. ACC activity is acutely regulated by phosphorylation/dephosphorylation. AMP-activated protein kinase phosphorylates ACC and inhibits enzyme activity (11). In the fed state, excess glucose must be converted to FAs for energy storage in the form of TGs. Increased insulin signaling in the fed state res...

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Section: Discussionmentioning

confidence: 95%

Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis

Kim

Moon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

124

137

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“…Even though the exact biochemical function is not known, S14 encodes for a nuclear protein that is closely associated with the regulation of fatty acid synthesis in adipose and mammary tissue (Zhu et al, 2005;Anderson et al, 2009) in rodents. Collectively, these observations suggest that S14 may be an important component of the mechanism involved in the decrease in mammary lipogenesis in ruminants fed diets inducing MFD or in response to trans-10, cis-12 CLA.…”

Section: Nutritional Regulation Of the Ruminant Mammary Transcriptomementioning

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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“…Knock-down of S14 in hepatocyte culture resulted in decreased expression of lipogenic enzymes (reviewed by Cunningham et al, 1998), but the S14 knockout mouse had increased hepatic lipogenesis (Zhu et al, 2001). Of special interest in considering possible relevance to MFD, S14 knock-out mice had a 62% reduction in mammary lipogenesis and a 26% reduction in milk clot triglyceride concentration, which was predominantly due to decreased de novo fatty acid synthesis; however, activities of mammary lipogenic enzymes were unaltered (Zhu et al, 2005).…”

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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The Spot 14 Protein Is Required for de Novo Lipid Synthesis in the Lactating Mammary Gland

Cited by 85 publications

References 37 publications

Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis

Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis

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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