Lipin-1 Phosphatidic Phosphatase Activity Modulates Phosphatidate Levels to Promote Peroxisome Proliferator-activated Receptor γ (PPARγ) Gene Expression during Adipogenesis

Zhang, Peixiang; Takeuchi, Keigo; Csáki, L; Reue, Karen

doi:10.1074/jbc.m111.296681

Cited by 73 publications

(86 citation statements)

References 66 publications

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“…Besides LD expansion, PA has also been implicated in adipocyte differentiation (32)(33)(34). We hypothesized that the accumulation of PA in the ER and nuclear membrane upon CDS1/2 depletion could inhibit adipocyte differentiation by possibly interfering with PPAR function.…”

Section: Downregulation Of Cds1 Inhibits Adipocyte Differentiationmentioning

confidence: 99%

CDP-diacylglycerol synthases regulate the growth of lipid droplets and adipocyte development

Kapterian

et al. 2016

Journal of Lipid Research

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Lipid droplets (LDs) are highly dynamic organelles that play a central role in mammalian energy storage. LDs are also involved in many cellular functions, including protein storage and degradation, and membrane and lipid trafficking (1-4). Each LD contains a hydrophobic neutral lipid core enclosed by a phospholipid monolayer (5). In mammals, the lipid core comprises mainly triacylglycerols (TAGs) and cholesteryl esters. The molecular events underlying the biogenesis of LDs remain to be determined (6). While several models have been proposed, the prevailing view is that LDs originate and bud from the endoplasmic reticulum (ER), followed by expansion and maturation (7). A recent study suggests that the fat storage-inducing transmembrane proteins are required for proper budding of LDs from the ER (8). The growth of LDs is not fully understood, as the size of LDs varies within different tissues and even within the same cell type (9). Recent studies have established the Cide family proteins, Cidec/FSP27 in particular, as key regulators of LD growth/fusion in adipocytes (10, 11). Phospholipids, especially phosphatidylcholine (PC) and phosphatidic acid (PA), also appear to be important regulators of LD growth and proliferation, as a decrease in PC or an increase in PA can both result in the formation of giant or "supersized" LDs (1, 9, 12, 13). LDs can also grow by lipid synthesis in situ, as TAG synthesis enzymes can relocate from the ER to the LD surface to mediate LD growth (14). Despite these important findings, Abstract The expansion of lipid droplets (LDs) and the differentiation of preadipocytes are two important aspects of mammalian lipid storage. In this study, we examined the role of CDP-diacylglycerol (DAG) synthases (CDSs), encoded by CDS1 and CDS2 genes in mammals, in lipid storage. CDS enzymes catalyze the formation of CDP-DAG from phosphatidic acid (PA). Knocking down either CDS1 or CDS2 resulted in the formation of giant or supersized LDs in cultured cells. Moreover, depleting CDS1 almost completely blocked the differentiation of 3T3-L1 preadipocytes, whereas depleting CDS2 had a moderate inhibitory effect on adipocyte differentiation. The levels of many PA species were significantly increased upon knocking down CDS1. In contrast, only a small number of PA species were increased upon depleting CDS2. Importantly, the amount of PA in the endoplasmic reticulum was dramatically increased upon knocking down CDS1 or CDS2. Our results suggest that the changes in PA level and localization may underlie the formation of giant LDs as well as the block in adipogenesis in CDS-deficient cells. We have therefore identified CDS1 and CDS2 as important novel regulators of lipid storage, and these results highlight the crucial role of phospholipids in mammalian lipid storage.-Qi, Y., T.

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Section: Downregulation Of Cds1 Inhibits Adipocyte Differentiationmentioning

confidence: 99%

CDP-diacylglycerol synthases regulate the growth of lipid droplets and adipocyte development

Kapterian

et al. 2016

Journal of Lipid Research

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“…7) (8). It should also be noted that AGPAT2 and LPIN1 are key mammalian genes linked to severe generalized lipodystrophy, and genetic ablation of either gene also causes accumulation of PA, which could account for the failure in adipogenesis (32)(33)(34). Therefore, PA toxicity appears to be a common theme in a few models of mammalian lipodystrophy.…”

Section: Seipin and Ppar-gmentioning

confidence: 99%

Adipose-Specific Knockout of Seipin/Bscl2 Results in Progressive Lipodystrophy

et al. 2014

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Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is the most severe form of human lipodystrophy, characterized by an almost complete loss of adipose tissue and severe insulin resistance. BSCL2 is caused by loss-of-function mutations in the BSCL2/SEIPIN gene, which is upregulated during adipogenesis and abundantly expressed in the adipose tissue. The physiological function of SEIPIN in mature adipocytes, however, remains to be elucidated. Here, we generated adipose-specific Seipin knockout (ASKO) mice, which exhibit adipocyte hypertrophy with enlarged lipid droplets, reduced lipolysis, adipose tissue inflammation, progressive loss of white and brown adipose tissue, insulin resistance, and hepatic steatosis. Lipidomic and microarray analyses revealed accumulation/imbalance of lipid species, including ceramides, in ASKO adipose tissue as well as increased endoplasmic reticulum stress. Interestingly, the ASKO mice almost completely phenocopy the fat-specific peroxisome proliferator–activated receptor-γ (Pparγ) knockout (FKO-γ) mice. Rosiglitazone treatment significantly improved a number of metabolic parameters of the ASKO mice, including insulin sensitivity. Our results therefore demonstrate a critical role of SEIPIN in maintaining lipid homeostasis and function of adipocytes and reveal an intimate relationship between SEIPIN and PPAR-γ.

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“…Growing evidence suggests that in addition to the synthesis of glycerolipids, an important role of lipin-1 is to prevent the accumulation of lipid intermediates in the cell. Lipin-1-deficient tissues in mouse, and lipin-1-deficient muscle in humans, accumulate PA, the substrate of lipin PAP activity (10,13,14). PA accumulation in lipin-1-deficient adipose tissue and Schwann cells leads to inappropriate activation of the MAPK/ERK signaling pathway and inhibition of cellular differentiation, contributing to the lipodystrophy and peripheral neuropathy occurring in these mice (13,14).…”

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confidence: 99%

Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum

Dwyer

Donkor

Zhang

et al. 2012

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

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The three lipin phosphatidate phosphatase (PAP) enzymes catalyze a step in glycerolipid biosynthesis, the conversion of phosphatidate to diacylglycerol. Lipin-1 is critical for lipid synthesis and homeostasis in adipose tissue, liver, muscle, and peripheral nerves. Little is known about the physiological role of lipin-2, the predominant lipin protein present in liver and the deficient gene product in the rare disorder Majeed syndrome. By using lipin-2–deficient mice, we uncovered a functional relationship between lipin-1 and lipin-2 that operates in a tissue-specific and age-dependent manner. In liver, lipin-2 deficiency led to a compensatory increase in hepatic lipin-1 protein and elevated PAP activity, which maintained lipid homeostasis under basal conditions, but led to diet-induced hepatic triglyceride accumulation. As lipin-2–deficient mice aged, they developed ataxia and impaired balance. This was associated with the combination of lipin-2 deficiency and an age-dependent reduction in cerebellar lipin-1 levels, resulting in altered cerebellar phospholipid composition. Similar to patients with Majeed syndrome, lipin-2–deficient mice developed anemia, but did not show evidence of osteomyelitis, suggesting that additional environmental or genetic components contribute to the bone abnormalities observed in patients. Combined lipin-1 and lipin-2 deficiency caused embryonic lethality. Our results reveal functional interactions between members of the lipin family in vivo, and a unique role for lipin-2 in central nervous system biology that may be particularly important with advancing age. Additionally, as has been observed in mice and humans with lipin-1 deficiency, the pathophysiology in lipin-2 deficiency is associated with dysregulation of lipid intermediates.

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Lipin-1 Phosphatidic Phosphatase Activity Modulates Phosphatidate Levels to Promote Peroxisome Proliferator-activated Receptor γ (PPARγ) Gene Expression during Adipogenesis

Cited by 73 publications

References 66 publications

CDP-diacylglycerol synthases regulate the growth of lipid droplets and adipocyte development

CDP-diacylglycerol synthases regulate the growth of lipid droplets and adipocyte development

Adipose-Specific Knockout of Seipin/Bscl2 Results in Progressive Lipodystrophy

Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum

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