Adipose triglyceride lipase affects triacylglycerol metabolism at brain barriers

Etschmaier, Karoline; Becker, Tatjana; Eichmann, Thomas O.; Schweinzer, Cornelia; Scholler, Monika; Tam‐Amersdorfer, Carmen; Poeckl, Michael; Schuligoi, Rufina; Kober, Alexandra; Manavalan, Anil Paul Chirackal; Rechberger, Gerald; Streith, Ingo E.; Zechner, Rudolf; Zimmermann, R.; Panzenboeck, Ute

doi:10.1111/j.1471-4159.2011.07498.x

Cited by 63 publications

(50 citation statements)

References 56 publications

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“…−/− mice have elevated TAGs in brain tissue, but these changes are restricted to barrier regions of the CNS (e.g., cerebrovascular cells, choroid plexus) (29). LDs were not found to accumulate in neurons of PNPLA2 −/− mice, indicating that these cells may express distinct TAG hydrolytic enzymes.…”

Section: Discussionmentioning

confidence: 91%

The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase

Inloes

Hsu

Dix

et al. 2014

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

151

184

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Complex hereditary spastic paraplegia (HSP) is a genetic disorder that causes lower limb spasticity and weakness and intellectual disability. Deleterious mutations in the poorly characterized serine hydrolase DDHD2 are a causative basis for recessive complex HSP. DDHD2 exhibits phospholipase activity in vitro, but its endogenous substrates and biochemical functions remain unknown. Here, we report the development of DDHD2 −/− mice and a selective, in vivo-active DDHD2 inhibitor and their use in combination with mass spectrometry-based lipidomics to discover that DDHD2 regulates brain triglycerides (triacylglycerols, or TAGs). DDHD2 −/− mice show age-dependent TAG elevations in the central nervous system, but not in several peripheral tissues. Large lipid droplets accumulated in DDHD2 −/− brains and were localized primarily to the intracellular compartments of neurons. These metabolic changes were accompanied by impairments in motor and cognitive function. Recombinant DDHD2 displays TAG hydrolase activity, and TAGs accumulated in the brains of wild-type mice treated subchronically with a selective DDHD2 inhibitor. These findings, taken together, indicate that the central nervous system possesses a specialized pathway for metabolizing TAGs, disruption of which leads to massive lipid accumulation in neurons and complex HSP syndrome. D etermining the genetic basis for rare hereditary human diseases has benefited from advances in DNA sequencing technologies (1). As a greater number of disease-causing mutations are mapped, however, it is also becoming apparent that many of the affected genes code for poorly characterized proteins. Assigning biochemical and cellular functions to these proteins is critical to achieve a deeper mechanistic understanding of human genetic disorders and for identifying potential treatment strategies.Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurologic syndrome marked by spasticity and lower extremity weakness (2). Many genetic types of HSP have been identified and are numbered according to their order of discovery [spastic paraplegia (SPG) 1-72] (2, 3). Of these genetic variants, more than 40 have been mapped to causative mutations in protein-coding genes. HSP genes code for a wide range of proteins that do not conform to a single sequence-or function-related class. A subset of HSP genes, including PNPLA6 (or neuropathytarget esterase) (SPG39) (4), DDHD1 (SPG28) (5), and DDHD2 (SPG54) (3, 6-8), code for serine hydrolases. These enzymes have been designated as (lyso)phospholipases based on in vitro substrate assays (9-11), but their endogenous substrates and physiological functions remain poorly understood. The mutational landscape that affects these lipid hydrolases to cause recessive HSP is complex but collectively represents a mix of null and putatively null and/or functional mutations. Moreover, the type of HSP appears to differ in each case, with DDHD1 mutations causing uncomplicated HSP, whereas PNPLA6 and DDHD2 mutations lead to complex forms of the disease that...

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Section: Discussionmentioning

confidence: 91%

The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase

Inloes

Hsu

Dix

et al. 2014

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

151

184

View full text Add to dashboard Cite

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“…4B to D). Changes in triacylglycerol content in the brain were likely in ependymal cells (44). Because the metabolite data suggested an increase in phospholipase activity, we measured brain cytosolic phospholipase A 2 activity in control and Acot7 NϪ/Ϫ brains.…”

Section: Resultsmentioning

confidence: 99%

Acyl Coenzyme A Thioesterase 7 Regulates Neuronal Fatty Acid Metabolism To Prevent Neurotoxicity

Ellis

Wong

Wolfgang

2013

Molecular and Cellular Biology

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Numerous neurological diseases are associated with dysregulated lipid metabolism; however, the basic metabolic control of fatty acid metabolism in neurons remains enigmatic. Here we have shown that neurons have abundant expression and activity of the long-chain cytoplasmic acyl coenzyme A (acyl-CoA) thioesterase 7 (ACOT7) to regulate lipid retention and metabolism. Unbiased and targeted metabolomic analysis of fasted mice with a conditional knockout of ACOT7 in the nervous system, Acot7 N؊/؊ , revealed increased fatty acid flux into multiple long-chain acyl-CoA-dependent pathways. The alterations in brain fatty acid metabolism were concomitant with a loss of lean mass, hypermetabolism, hepatic steatosis, dyslipidemia, and behavioral hyperexcitability in Acot7 N؊/؊ mice. These failures in adaptive energy metabolism are common in neurodegenerative diseases. In agreement, Acot7 N؊/؊ mice exhibit neurological dysfunction and neurodegeneration. These data show that ACOT7 counterregulates fatty acid metabolism in neurons and protects against neurotoxicity. Neurons have a unique lipid composition that is critical for the development and function of the nervous system, and defects in lipid metabolism result in severe and debilitating neurological disease; however, there is a dearth of understanding about how neurons uniquely regulate intracellular fatty acid (FA) metabolism. There are numerous inborn errors of lipid metabolism that have clear neuropathological outcomes. Apart from these inborn errors of metabolism, it is becoming increasingly evident that many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), have underlying metabolic dysfunction that often involves dysregulated lipid metabolism (1-5). A better understanding of neuronal metabolism is required to provide insight into neurological function and pathology, since dysregulated neurometabolism may contribute to the progression of diabetes and obesity and hasten neurodegeneration (6-8).Fatty acid metabolism in the nervous system has been shown to directly and profoundly regulate multiple aspects of animal physiology and behavior (9-14). Furthermore, ion channels that play a role in neuronal activation have been shown to be regulated by lipids either directly or indirectly (15)(16)(17)(18)(19)(20). Fatty acids are precursors for membrane biosynthesis, signaling lipids, posttranslational modification (e.g., palmitoylation), energy storage, and energy production. Although most neurons are not thought to rely on fatty acids to meet their cellular bioenergetic requirements, the brain has a unique fatty acid composition and metabolism that are critical for neural function. Due in part to the incredible heterogeneity of neurons themselves and the diversity of neuronal cell types in general, the means by which any neuronal population obtains or utilizes fatty acids is poorly understood.Fatty acids either made de novo or taken up from the diet require ligation to coenzyme A (CoA) for their cellular r...

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“…Ependymal cells are a major source of local signals, constituting approximately 25% of cells within the SVZ niche (Doetsch et al, 1997) and surrounding NSCs in pinwheel (legend continued on next page) structures within the walls of the lateral ventricles (Mirzadeh et al, 2008). Ependymal cells provide a critical interface for the exchange of ions, macromolecules, and immune cells between the brain and the circulating CSF, secrete a variety of molecules that regulate NSC activity, and have been identified as sites of lipid synthesis and storage (Bouab et al, 2011;Etschmaier et al, 2011;Hamilton et al, 2010). Interestingly, AD is associated with both declines in neurogenesis-regulated cognitive processes and aberrations in lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer’s Disease

et al. 2015

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Lipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Here, we uncover a fatty acid-mediated mechanism suppressing endogenous NSC activity in Alzheimer's disease (AD). We found that postmortem AD brains and triple-transgenic Alzheimer's disease (3xTg-AD) mice accumulate neutral lipids within ependymal cells, the main support cell of the forebrain NSC niche. Mass spectrometry and microarray analyses identified these lipids as oleic acid-enriched triglycerides that originate from niche-derived rather than peripheral lipid metabolism defects. In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit NSC proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis rescued proliferative defects in both adult neurogenic niches of 3xTg-AD mice. These studies support a pathogenic mechanism whereby AD-induced perturbation of niche fatty acid metabolism suppresses the homeostatic and regenerative functions of NSCs.

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Adipose triglyceride lipase affects triacylglycerol metabolism at brain barriers

Cited by 63 publications

References 56 publications

The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase

The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase

Acyl Coenzyme A Thioesterase 7 Regulates Neuronal Fatty Acid Metabolism To Prevent Neurotoxicity

Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer’s Disease

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