Lipid homeostasis is maintained through the coordination of lipid metabolism in various tissues, including adipose tissue and the liver. The disruption of lipid homeostasis often results in the ...development of metabolic disorders such as obesity, diabetes mellitus, liver steatosis, and cardiovascular diseases. Cell death-inducing DNA fragmentation factor 45-like effector family proteins, including Cidea, Cideb, and Fsp27 (Cidec), are emerging as important regulators of various lipid metabolic pathways and play pivotal roles in the development of metabolic disorders. This review summarizes the latest cell death-inducing DNA fragmentation factor 45-like effector protein discoveries related to the control of lipid metabolism, with emphasis on the role of these proteins in lipid droplet growth in adipocytes and in the regulation of very low-density lipoprotein lipidation and maturation in hepatocytes.
Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been ...elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease.
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•Heterogeneity and plasticity of non-parenchymal cells in healthy and NASH liver•Landscape of intrahepatic ligand-receptor signaling at single-cell resolution•Emergence of Trem2+ NASH-associated macrophages (NAMs) in mouse and human NASH•Stellakine secretion and contractile response to vasoactive hormones by HSCs
This work illustrates the heterogeneity of liver non-parenchymal cells (NPCs) and their reprogramming during NASH pathogenesis. Using single-cell RNA-sequencing analysis, the authors mapped the landscape of the intrahepatic ligand-receptor signaling network and revealed two fundamental aspects of HSC biology: stellakine secretion and contractile response to vasoactive hormones. Hepatic vascular dysfunction and emergence of Trem2+ NASH-associated macrophages (NAMs) are two conserved features of mouse and human NASH.
Control of lipid droplet fusion and growth by CIDE family proteins Gao, Guangang; Chen, Feng-Jung; Zhou, Linkang ...
Biochimica et biophysica acta. Molecular and cell biology of lipids,
October 2017, 2017-Oct, 2017-10-00, 20171001, Letnik:
1862, Številka:
10
Journal Article
Recenzirano
Cell death-inducing DFF45-like effector (CIDE) family proteins including Cidea, Cideb and Cidec/Fsp27 are expressed in many different tissues and are known as lipid droplet (LD)-and ER-associated ...proteins. Systematic analyses using genetically modified animal models have demonstrated that CIDE proteins play important roles in regulating various aspects of lipid homeostasis, including lipid storage, lipolysis and lipid secretion. Recent research in ours and other laboratories has revealed that CIDE proteins are crucial regulators of LD fusion and growth in the adipose tissue, liver, skin and mammary glands. CIDE-mediated LD fusion and growth is different from other membrane fusions in that it requires CIDE proteins to be enriched and clustered at the LD-LD contact sites (LDCS). The enriched CIDE proteins then allow the recruitment of other proteins to the LDCS and the formation of potential fusion pores. Neutral lipids in the smaller LDs of the contacted pair are transferred to the larger LDs, owing to the internal pressure difference, thus resulting in the fusion and growth of the LDs. This review summarizes the physiological roles of CIDE proteins in controlling lipid homeostasis, insulin sensitivity and the development of metabolic diseases including obesity, diabetes and fatty liver, with a particular focus on the role of CIDE proteins in controlling LD fusion and growth. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink.
•CIDEs control lipid storage and regulate insulin sensitivity.•CIDEs control LD fusion and growth.•Transcriptional and post-translational regulation of CIDEs.
The fibroblast cell line of 3T3-L1 was used as a cell model for screening and evaluating the feasibility of probiotic components in improving animal lipid metabolisms. The extracts from 12 ...Lactobacillus strains caused significantly reduced triacylglycerol (TAG) accumulation but with severe inflammation induction in 3T3-L1 adipocytes. Interestingly, exopolysaccharides (EPS) from LGG (Lactobacillus rhamnosus GG) significantly decreased the TAG accumulation without any inflammation. The anti-obesity effect of EPS was confirmed in high-fat-diets feeding mice. Fat pads of mice injected with EPS (50 mg/kg) every two days for two weeks were significantly reduced with much smaller adipocytes, compared with the counterparts. The levels of TAG and cholesterol ester in liver, as well as serum TAG, were decreased in EPS injected mice. In addition, down-regulated inflammation was observed in adipose tissue and liver. Interestingly, the expression of TLR2 in adipose tissue and 3T3-L1 cells was significantly increased by EPS addition. Moreover, the reverse of TAG accumulation in TLR2 knockdown 3T3-L1 in the presence of EPS confirmed that the inhibition effect of EPS on adipogenesis was mediated by TLR2. EPS from LGG has the potential for therapeutic development to intervene lipid metabolic disorders in mammals.
Lipid droplets (LDs) are evolutionarily conserved organelles that play important roles in cellular metabolism. Each LD is enclosed by a monolayer of phospholipids, distinct from bilayer membranes. ...During LD biogenesis and growth, this monolayer of lipids expands by acquiring phospholipids from the endoplasmic reticulum (ER) through nonvesicular mechanisms. Here, in a mini-screen, we find that ORP5, an integral membrane protein of the ER, can localize to ER-LD contact sites upon oleate loading. ORP5 interacts with LDs through its ligand-binding domain, and ORP5 deficiency enhances neutral lipid synthesis and increases the size of LDs. Importantly, there is significantly more phosphatidylinositol-4-phosphate (PI(4)P) and less phosphatidylserine (PS) on LDs in ORP5-deficient cells than in normal cells. The increased presence of PI(4)P on LDs in ORP5-deficient cells requires phosphatidylinositol 4-kinase 2-α. Our results thus demonstrate the existence of PI(4)P on LDs and suggest that LD-associated PI(4)P may be primarily used by ORP5 to deliver PS to LDs.
Insulin-stimulated hepatic glycogen synthesis is central to glucose homeostasis. Here, we show that PPP1R3G, a regulatory subunit of protein phosphatase 1 (PP1), is directly phosphorylated by AKT. ...PPP1R3G phosphorylation fluctuates with fasting-refeeding cycle and is required for insulin-stimulated dephosphorylation, i.e., activation of glycogen synthase (GS) in hepatocytes. In this study, we demonstrate that knockdown of PPP1R3G significantly inhibits insulin response. The introduction of wild-type PPP1R3G, and not phosphorylation-defective mutants, increases hepatic glycogen deposition, blood glucose clearance, and insulin sensitivity in vivo. Mechanistically, phosphorylated PPP1R3G displays increased binding for, and promotes dephosphorylation of, phospho-GS. Furthermore, PPP1R3B, another regulatory subunit of PP1, binds to the dephosphorylated GS, thereby relaying insulin stimulation to hepatic glycogen deposition. Importantly, this PP1-mediated signaling cascade is independent of GSK3. Therefore, we reveal a regulatory axis consisting of insulin/AKT/PPP1R3G/PPP1R3B that operates in parallel to the GSK3-dependent pathway, controlling glycogen synthesis and glucose homeostasis in insulin signaling.
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•PPP1R3G is directly phosphorylated by AKT in response to insulin or feeding•PPP1R3G phosphorylation accelerates postprandial glycogenesis and glucose clearance•Phosphorylation of PPP1R3G enhances its association with p-GS•PPP1R3B acts downstream of PPP1R3G to relay insulin signals for glycogen synthesis
Compelling evidence suggests that a GSK3-independent pathway exists, linking insulin signaling with glycogen synthesis. However, the molecular mechanism underlying this pathway remains unclear. Li et al. reveal the presence of an axis for insulin signaling consisting of insulin/AKT/PPP1R3G/PPP1R3B that controls glycogen synthesis and glucose homeostasis in parallel to the GSK3-dependent pathway.
Rab GTPases, by targeting to specific membrane compartments, play essential roles in membrane trafficking. Lipid droplets (LDs) are dynamic subcellular organelles whose growth is closely linked to ...obesity and hepatic steatosis. Fsp27 is shown to be required for LD fusion and growth by enriching at LD-LD contact sites. Here, we identify Rab8a as a direct interactor and regulator of Fsp27 in mediating LD fusion in adipocytes. Knockdown of Rab8a in the livers of ob/ob mice results in the accumulation of smaller LDs and lower hepatic lipid levels. Surprisingly, it is the GDP-bound form of Rab8a that exhibits fusion-promoting activity. We further discover AS160 as the GTPase activating protein (GAP) for Rab8a, which forms a ternary complex with Fsp27 and Rab8a to positively regulate LD fusion. MSS4 antagonizes Fsp27-mediated LD fusion activity through Rab8a. Our results have thus revealed a mechanistic signaling circuit controlling LD fusion and fatty liver formation.
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•Identification of Rab8a as an activator of Fsp27-mediated LD fusion and growth•GDP-bound Rab8a is enriched at the LD contact sites and promotes LD fusion•AS160 acts as a Rab8a GAP to enhance Fsp27-mediated LD fusion•MSS4, known to stabilize nucleotide-free Rab8a, restrains Rab8a-mediated LD fusion
Wu et al. find that GDP-bound Rab8a is enriched at lipid droplet (LD) contact sites and binds Fsp27 to enhance its LD fusion activity. The Rab8a GAP AS160 activates this function, whereas MSS4 (which stabilizes nucleotide-free Rab8a GTPase) attenuates it. These findings reveal a regulatory circuit controlling LD fusion.
High levels of dietary saturated fat have been closely associated with the development of hepatic steatosis, but the factors that mediate this process remain elusive. Here, we observed that the level ...of cell death‐inducing DNA fragmentation factor‐alpha‐like effector a (Cidea) expression was highly correlated with the severity of hepatic steatosis in humans. Overexpression of Cidea in mouse liver resulted in increased hepatic lipid accumulation and the formation of large lipid droplets (LDs). In contrast, mice with a Cidea deficiency had decreased lipid accumulation and alleviated hepatic steatosis when they received a high‐fat‐diet feeding or in ob/ob mice. Furthermore, the knockdown of Cidea in livers of ob/ob mice resulted in significantly reduced hepatic lipid accumulation and smaller LDs. Importantly, we observed that Cidea expression in hepatocytes was specifically induced by saturated fatty acids (FAs), and such induction was reduced when sterol response element‐binding protein (SREBP)1c was knocked down. In contrast, the overexpression of SREBP1c restored the saturated FA‐induced expression of Cidea. In addition, we observed that the stability of Cidea protein in hepatocytes increased significantly in response to treatment with FAs. Conclusion: Cidea plays critical roles in promoting hepatic lipid accumulation and in the development of hepatic steatosis by acting as a sensor that responds to diets that contain FAs. (Hepatology 2012;56:95–107)
Excess lipid storage in adipose tissue results in the development of obesity and other metabolic disorders including diabetes, fatty liver and cardiovascular diseases. The lipid droplet (LD) is an ...important subcellular organelle responsible for lipid storage. We previously observed that Fsp27, a member of the CIDE family proteins, is localized to LD-contact sites and promotes atypical LD fusion and growth. Cidea, a close homolog of Fsp27, is expressed at high levels in brown adipose tissue. However, the exact role of Cidea in promoting LD fusion and lipid storage in adipose tissue remains unknown. Here, we expressed Cidea in Fsp27-knockdown adipocytes and observed that Cidea has similar activity to Fsp27 in promoting lipid storage and LD fusion and growth. Next, we generated
Cidea
and
Fsp27
double-deficient mice and observed that these animals had drastically reduced adipose tissue mass and a strong lean phenotype. In addition,
Cidea/Fsp27
double-deficient mice had improved insulin sensitivity and were intolerant to cold. Furthermore, we observed that the brown and white adipose tissues of
Cidea/Fsp27
double-deficient mice had significantly reduced lipid storage and contained smaller LDs compared to those of
Cidea
or
Fsp27
single deficient mice. Overall, these data reveal an important role of Cidea in controlling lipid droplet fusion, lipid storage in brown and white adipose tissue, and the development of obesity.
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