Partitioning of MLX-Family Transcription Factors to Lipid Droplets Regulates Metabolic Gene Expression

Mejhert, Niklas; Kuruvilla, Leena; Gabriel, Katlyn R.; Elliott, Shane D.; Guie, Marie-Aude; Wang, Huajin; Lai, Zon Weng; Lane, Elizabeth A.; Christiano, Romain; Danial, Nika N.; Farese, Robert V.; Walther, Tobias C.

doi:10.1016/j.molcel.2020.01.014

Cited by 95 publications

(135 citation statements)

References 109 publications

(129 reference statements)

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“…Indeed, these findings are consistent with glucose-mediated activation of MLX family of transcription factors (Kawaguchi et al, 2001;Ma et al, 2005), including ChREBP, and target genes that promote de novo lipogenesis in BAT (Mottillo et al, 2014;Sanchez-Gurmaches et al, 2018;Trayhurn, 1979;Yu et al, 2002). This finding is also consistent with our recent report of increased expression of ChREBP/MLX-target genes in cells lacking LDs through DGAT inhbition (Mejhert et al, 2020). Moreover, they agree with previous studies that suggest a feedback mechanism correlating reduced DGAT activity with inhibiton of the SREBP1mediated lipogenic pathway (Chitraju et al, 2017;Choi et al, 2007;Monetti et al, 2007).…”

Section: Discussionsupporting

confidence: 92%

Lipid Droplets in Brown Adipose Tissue Are Dispensable for Cold-Induced Thermogenesis

Chitraju

Fischer

Farese

et al. 2020

Preprint

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Brown adipocytes store metabolic energy as triglycerides (TG) in multilocular lipid droplets (LDs). Fatty acids released from brown adipocyte LDs by lipolysis are thought to activate and fuel UCP1-mediated thermogenesis. Here we test this hypothesis by preventing fatty acid storage in murine brown adipocytes through brown adipose tissue (BAT)-specific deletions of the TG synthesis enzymes, DGAT1 and DGAT2 (BA-DGAT KO). Despite the absence of LDs, BA-DGAT KO mice had functional BAT and maintained euthermia during acute or chronic cold exposure. As apparent adaptations to the lack of TG, brown adipocytes of BA-DGAT KO mice appear to utilize circulating glucose and fatty acids, as well as stored glycogen to fuel thermogenesis. Moreover, BA-DGAT KO mice were resistant to diet-induced glucose intolerance, likely due to increased glucose disposal by BAT. Thus, surprisingly, TGs in BAT are dispensable for its function, in part through adaptations to utilize other fuel sources.

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Section: Discussionsupporting

confidence: 92%

Lipid Droplets in Brown Adipose Tissue Are Dispensable for Cold-Induced Thermogenesis

Chitraju

Fischer

Farese

et al. 2020

Preprint

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“…We conclude that PISD-LD-GFP localizes in part to lipid droplets. Importantly, recent proteomics-based inventories of LD proteins in multiple cell types (U2OS, THP-1, SUM159) identified native PISD in purified lipid droplet fractions (Bersuker et al, 2018;Mejhert et al, 2020).…”

Section: An Alternatively Spliced Variant Of Pisd Localizes To the LImentioning

confidence: 99%

“…Several types of structural features of LD proteins have been identified that confer LD targeting (Kory et al, 2016). Some amphipathic alpha helices confer reversible targeting to the LD surface from the cytosol/aqueous phase, and a second type of LD targeting determinant consists of a hydrophobic segment that forms a lipid-embedded hairpin (Mejhert et al, 2020).…”

Section: Pisd-ld Possesses Overlapping Ld and Mitochondrion Targetingmentioning

confidence: 99%

Conditional targeting of phosphatidylserine decarboxylase to lipid droplets

Kumar

Chitraju

Farese

et al. 2020

Preprint

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Phosphatidylethanolamine is an abundant component of most cellular membranes whose physical and chemical properties modulate multiple aspects of organelle membrane dynamics. An evolutionarily ancient mechanism for producing phosphatidylethanolamine is to decarboxylate phosphatidylserine and the enzyme catalyzing this reaction, phosphatidylserine decarboxylase, localizes to the inner membrane of the mitochondrion. We characterize a second form of phosphatidylserine decarboxylase, termed PISD-LD, that is generated by alternative splicing of PISD pre-mRNA and localizes to lipid droplets and to mitochondria. Sub-cellular targeting is controlled by a common segment of PISD-LD that is distinct from the catalytic domain and is regulated by nutritional state. Growth conditions that promote neutral lipid storage in lipid droplets favors targeting to lipid droplets, while targeting to mitochondria is favored by conditions that promote consumption of lipid droplets. Depletion of both forms of phosphatidylserine decarboxylase impairs triacylglycerol synthesis when cells are challenged with free fatty acid, indicating a crucial role phosphatidylserine decarboxylase in neutral lipid storage. The results reveal a previously unappreciated role for phosphatidylserine decarboxylase in lipid droplet biogenesis.

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“…It is now well-established that LDs can transiently accumulate proteins from other cellular compartments (Welte, 2007). This has been particularly documented for a number of proteins involved in nuclei acid binding/transcriptional regulation: For example, in mammalian cells, MLX and Perilipin 5 can either be present on LDs or move into the nucleus to regulate transcription (Gallardo-Montejano et al, 2016;Mejhert et al, 2020). In bacteria, the transcriptional regulator MLDSR (microorganism lipid droplet small regulator) is sequestered to LDs under stress conditions (Zhang et al, 2017).…”

Section: Broader Insights Into Protein Sequestrationmentioning

confidence: 99%

“…Sequestration of the ER protein Sturkopf to LDs has been proposed to mitigate its repressive effects on an ER-associated enzyme (Werthebach et al, 2019). And a number of proteins involved in transcriptional regulation can be sequestered on LDs in bacteria, fungi, and mammalian cells (Aramburu et al, 2006;Gallardo-Montejano et al, 2016;Mejhert et al, 2020;Romanauska & Kohler, 2018;Zhang et al, 2017). However, in only a few cases is the function of protein sequestration on LDs understood at a molecular level.…”

Section: Introductionmentioning

confidence: 99%

Sequestration to lipid droplets promotes histone availability by preventing turnover of excess histones

Stephenson

Thomalla

Chen

et al. 2020

Preprint

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Because dearth and overabundance of histones result in cellular defects, histone synthesis and demand are typically tightly coupled. In Drosophila embryos, histones H2B/H2A/H2Av accumulate on lipid droplets (LDs), cytoplasmic fat storage organelles. Without this binding, maternally provided H2B/H2A/H2Av are absent; however, the molecular basis of how LDs ensure histone storage is unclear. Using quantitative imaging, we uncover when during oogenesis these histones accumulate, and which step of accumulation is LD-dependent. LDs originate in nurse cells and are transported to the oocyte. Although H2Av accumulates on LDs in nurse cells, the majority of the final H2Av pool is synthesized in oocytes. LDs promote intercellular transport of the histone-anchor Jabba and thus its presence in the ooplasm. Jabba prevents ooplasmic H2Av from degradation, safeguarding the H2Av stockpile. Our findings provide insight into the mechanism for establishing histone stores during Drosophila oogenesis and shed light on the function of LDs as protein-sequestration sites.

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Partitioning of MLX-Family Transcription Factors to Lipid Droplets Regulates Metabolic Gene Expression

Cited by 95 publications

References 109 publications

Lipid Droplets in Brown Adipose Tissue Are Dispensable for Cold-Induced Thermogenesis

Lipid Droplets in Brown Adipose Tissue Are Dispensable for Cold-Induced Thermogenesis

Conditional targeting of phosphatidylserine decarboxylase to lipid droplets

Sequestration to lipid droplets promotes histone availability by preventing turnover of excess histones

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