The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response

Basseri, Sana; Lhoták, Šárka; Sharma, Arya M.; Austin, Richard C.

doi:10.1194/jlr.m900216-jlr200

Cited by 203 publications

(186 citation statements)

References 77 publications

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“…Additionally, it has been shown that the UPR is up-regulated during 3T3-L1 adipocyte differentiation (18). These findings suggest the possibility that these two events are functionally linked, with mitochondrial function being required for UPR induction and to sustain adiponectin secretion in differentiated adipocytes.…”

mentioning

confidence: 67%

Adenylate Kinase 2 Links Mitochondrial Energy Metabolism to the Induction of the Unfolded Protein Response

Burkart

Shi

Chouinard

et al. 2011

Journal of Biological Chemistry

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The unfolded protein response (UPR) is a homeostatic signaling mechanism that balances the protein folding capacity of the endoplasmic reticulum (ER) with the secretory protein load of the cell. ER protein folding capacity is dependent on the abundance of chaperones, which is increased in response to UPR signaling, and on a sufficient ATP supply for their activity. An essential branch of the UPR entails the splicing of XBP1 mRNA to form the XBP1 transcription factor. XBP1 has been shown to be required during adipocyte differentiation, enabling mature adipocytes to secrete adiponectin, and during differentiation of B cells into antibody-secreting plasma cells. Here we find that adenylate kinase 2 (AK2), a mitochondrial enzyme that regulates adenine nucleotide interconversion within the intermembrane space, is markedly induced during adipocyte and B cell differentiation. Depletion of AK2 by RNAi impairs adiponectin secretion in 3T3-L1 adipocytes, IgM secretion in BCL1 cells, and the induction of the UPR during differentiation of both cell types. These results reveal a new mechanism by which mitochondria support ER function and suggest that specific mitochondrial defects may give rise to impaired UPR signaling. The requirement for AK2 for UPR induction may explain the pathogenesis of the profound hematopoietic defects of reticular dysgenesis, a disease associated with mutations of the AK2 gene in humans.Cellular homeostasis depends on the continuous synthesis of transmembrane and secretory proteins to maintain cellular integrity and an appropriate extracellular environment. These proteins are translocated into the endoplasmic reticulum (ER) 2 for post-translational processing, involving the function of numerous chaperones that catalyze ATP-dependent protein folding. When the need for endoplasmic reticulum folding capacity rises (ER stress), a transient inhibition of protein synthesis is triggered followed by an increase in chaperone levels. This coordinated response is known as the unfolded protein response (UPR). When the UPR fails to resolve ER stress, a global response is triggered that can lead to apoptosis and is linked to multiple human pathologies (1-5).The UPR is initiated through three known signaling pathways, the PERK, ATF6, and IRE1 pathways (2, 6, 7). PERK activation transiently decreases protein synthesis, and ATF6 is proteolytically cleaved to form a transcription factor that induces chaperone transcription. IRE1 is a bifunctional kinase/site-specific endoribonuclease that catalyzes XBP1 mRNA splicing, generating a stable mRNA product (sXBP1) from which the transcription factor XBP1 is translated. Like ATF6, XBP1 induces chaperone transcription. An important feature of IRE1 is that, unlike other autophosphorylating kinases, IRE1 is not activated by self-phosphorylation but rather by the occupancy of its ATP binding site (8).Given the requirement for ATP in chaperone function and IRE1 activation, the initiation and maintenance of the UPR are likely to be influenced by cellular energy levels. Several o...

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mentioning

confidence: 67%

Adenylate Kinase 2 Links Mitochondrial Energy Metabolism to the Induction of the Unfolded Protein Response

Burkart

Shi

Chouinard

et al. 2011

Journal of Biological Chemistry

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“…ER stress has been shown to inhibit adipogenesis in vivo via unfolded protein responses (UPRs), such as phosphorylation of eIF2 and induction of CHOP, but not phosphorylation of IRE1 (35), whereas others demonstrate that these UPRs are required for adipogenesis both in vivo and in vitro (36). To interrogate whether ER stress was involved in siCDS1/2-induced suppression of adipocyte differentiation, we examined a variety of UPRs on day 0 of Lipidomic analysis of phospholipids in the LD fraction.…”

Section: Discussionmentioning

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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“…Furthermore, a clinical effect of 4-PBA in treatment of homozygous mutants suffering from ␤-thalassemia was demonstrated (27) and also a putative curative effect of 4-PBA in spinal muscular atrophy is currently under critical discussion (28,29). Various studies demonstrated the effect of the chemical chaperone 4-PBA in stabilizing protein conformation, improving ER folding capacity, facilitating the trafficking of mutant proteins, reducing ER stress, modulating the unfolded protein response, and thus improving protein homeostasis in ER storage diseases (25,30,31). For instance, 4-PBA has been shown to enhance in vitro and in vivo the adaptive capacity of the ER and to improve systemic insulin action in the setting of obesity-induced insulin resistance in type 2 diabetes (30).…”

Section: Discussionmentioning

confidence: 99%

No Amelioration of Uromodulin Maturation and Trafficking Defect by Sodium 4-Phenylbutyrate in Vivo

Kemter

Sklenak

Rathkolb

et al. 2014

Journal of Biological Chemistry

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The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response

Cited by 203 publications

References 77 publications

Adenylate Kinase 2 Links Mitochondrial Energy Metabolism to the Induction of the Unfolded Protein Response

Adenylate Kinase 2 Links Mitochondrial Energy Metabolism to the Induction of the Unfolded Protein Response

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

No Amelioration of Uromodulin Maturation and Trafficking Defect by Sodium 4-Phenylbutyrate in Vivo

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