lipogenesis (DNL) is a complex and highly regulated process in which carbohydrates from circulation are converted into fatty acids that are then used for synthesizing either triglycerides or other ...lipid molecules. Dysregulation of DNL contributes to human diseases such as obesity, type 2 diabetes, and cardiovascular diseases. Thus, the lipogenic pathway may provide a new therapeutic opportunity for combating various pathological conditions that are associated with dysregulated lipid metabolism. Hepatic DNL has been well documented, but lipogenesis in adipocytes and its contribution to energy homeostasis and insulin sensitivity are less studied. Recent reports have gained significant insights into the signaling pathways that regulate lipogenic transcription factors and the role of DNL in adipose tissues. In this review, we will update the current knowledge of DNL in white and brown adipose tissues with the focus on transcriptional, post-translational, and central regulation of DNL. We will also summarize the recent findings of adipocyte DNL as a source of some signaling molecules that critically regulate energy metabolism.
A treelike hybrid multi-cluster tool is composed of both single-arm and dual-arm cluster tools with a treelike topology. Scheduling such a tool is challenging. For a hybrid treelike multi-cluster ...tool whose bottleneck individual tool is process-bound, this work aims at finding its optimal one-wafer cyclic schedule. It is modeled with Petri nets such that a onewafer cyclic schedule is parameterized as its robots’ waiting time. Based on the model, this work proves the existence of its onewafer cyclic schedule that features with the ease of industrial implementation. Then, computationally efficient algorithms are proposed to find the minimal cycle time and optimal onewafer cyclic schedule. Multi-cluster tool examples are given to illustrate the proposed approach. The use of the found schedules enables industrial multi-cluster tools to operate with their highest productivity.
The worldwide increase in type 2 diabetes (T2D) is becoming a major health concern, thus searching for novel preventive and therapeutic strategies has become urgent. In last decade, the paralogous ...transcription factors MondoA and carbohydrate response element-binding protein (ChREBP) have been revealed to be central mediators of glucose sensing in multiple metabolic organs. Under normal nutrient conditions, MondoA/ChREBP plays vital roles in maintaining glucose homeostasis. However, under chronic nutrient overload, the dysregulation of MondoA/ChREBP contributes to metabolic disorders, such as insulin resistance (IR) and T2D. In this review, we aim to provide an overview of recent advances in the understanding of MondoA/ChREBP and its roles in T2D development. Specifically, we will briefly summarize the functional similarities and differences between MondoA and ChREBP. Then, we will update the roles of MondoA/ChREBP in four T2D-associated metabolic organs (i.e., the skeletal muscle, liver, adipose tissue, and pancreas) in physiological and pathological conditions. Finally, we will discuss the opportunities and challenges of MondoA/ChREBP as drug targets for anti-diabetes. By doing so, we highlight the potential use of therapies targeting MondoA/ChREBP to counteract T2D and its complications.
The sterol regulatory element-binding proteins (SREBPs) are a family of transcription factors best known for stimulating the expression of genes encoding key lipogenic enzymes. However, SREBP ...functions beyond lipid metabolism are less understood. Here, we show that hepcidin antimicrobial peptide (Hamp), encoding the hormone hepcidin essential for iron homeostasis and regulated by dietary iron and inflammation, is a target gene of the two SREBP isoforms SREBP-1a/c. We found that in tissue culture, mature, active, and nuclear forms of the SREBP-1a/c proteins induce endogenous Hamp gene expression and increase the Hamp promoter activity primarily via three regulatory sequences, including an E-box. Moreover, ChIP experiments revealed that SREBP-1a binds to the Hamp gene promoter. Overexpression of nuclear SREBP-1a under the control of the phosphoenolpyruvate carboxylase-1 (Pck1) promoter in mice increased hepatic Hamp mRNA and blood hepcidin levels, and as expected, caused fatty liver. Consistent with the known effects of Hamp up-regulation, SREBP-1a–overexpressing mice displayed signs of dysregulation in iron metabolism, including reduced serum iron and increased hepatic and splenic iron storage. Conversely, liver-specific depletion of the nuclear forms of SREBPs, as in SREBP cleavage-activating protein knockout mice, impaired lipopolysaccharide-induced up-regulation of hepatic Hamp. Together, these results indicate that the SREBP-1a/c transcription regulators activate hepcidin expression and thereby contribute to the control of mammalian iron metabolism.
In semiconductor manufacturing, there are wafer fabrication processes with wafer revisiting. Some of them must meet wafer residency time constraints. Taking atomic layer deposition (ALD) as a typical ...wafer revisiting process, this paper studies the challenging scheduling problem of single-arm cluster tools for the ALD process with wafer residency time constraints. It is found that there are only several scheduling strategies that are applicable to this problem and one needs to apply each of them to decide whether a feasible schedule can be found or not. This work, for each applicable strategy, performs the schedulability analysis and derives the schedulability conditions for such tools for the first time. It proposes scheduling algorithms to obtain an optimal schedule efficiently if such conditions are met. It finally gives illustrative examples to show the application of the proposed concepts and approach.
Altered lipid metabolism underlies several major human diseases, including obesity and type 2 diabetes. However, lipid metabolism pathophysiology remains poorly understood at the molecular level. ...Insulin is the primary stimulator of hepatic lipogenesis through activation of the SREBP-1c transcription factor. Here we identified cyclin-dependent kinase 8 (CDK8) and its regulatory partner cyclin C (CycC) as negative regulators of the lipogenic pathway in Drosophila, mammalian hepatocytes, and mouse liver. The inhibitory effect of CDK8 and CycC on de novo lipogenesis was mediated through CDK8 phosphorylation of nuclear SREBP-1c at a conserved threonine residue. Phosphorylation by CDK8 enhanced SREBP-1c ubiquitination and protein degradation. Importantly, consistent with the physiologic regulation of lipid biosynthesis, CDK8 and CycC proteins were rapidly downregulated by feeding and insulin, resulting in decreased SREBP-1c phosphorylation. Moreover, overexpression of CycC efficiently suppressed insulin and feeding-induced lipogenic gene expression. Taken together, these results demonstrate that CDK8 and CycC function as evolutionarily conserved components of the insulin signaling pathway in regulating lipid homeostasis.
In a multi-cluster tool, there may be both single and dual-arm cluster tools. Such a multi-cluster tool is called hybrid multi-cluster tool. To operate such a multi-cluster tool, one needs to ...coordinate different types of robots for accessing the shared buffering modules. Aiming at finding a one-wafer periodic schedule such that the lower bound of cycle time can be reached, this paper conducts a study on scheduling a hybrid multi-cluster tool with its bottleneck tool being process-bound. The tool is modeled by a kind of timed Petri net model. With this model, the scheduling problem is reduced to determining the robots' waiting time. Then, the conditions under which a one-wafer periodic schedule exists such that the lower bound of cycle time can be reached are presented. Based on them, a closed-form algorithm is given to check whether such a one-wafer periodic schedule exists. If so, it is found via simple calculation. Examples are given to show the application of the proposed method.
The E2F1 transcription factor can promote proliferation or apoptosis when activated, and is a key downstream target of the retinoblastoma tumour suppressor protein (pRB). Here we show that E2F1 is a ...potent and specific inhibitor of beta-catenin/T-cell factor (TCF)-dependent transcription, and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses beta-catenin activity in an adenomatous polyposis coli (APC)/glycogen synthase kinase-3 (GSK3)-independent manner, reducing the expression of key beta-catenin targets including c-MYC. This interaction explains why colorectal tumours, which depend on beta-catenin transcription for their abnormal proliferation, keep RB1 intact. Remarkably, E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. Thus, by retaining RB1 and amplifying CDK8, colorectal tumour cells select conditions that collectively suppress E2F1 and enhance the activity of beta-catenin.
Aging, chronic high-fat diet feeding, or housing at thermoneutrality induces brown adipose tissue (BAT) involution, a process characterized by reduction of BAT mass and function with increased lipid ...droplet size. Single nuclei RNA sequencing of aged mice identifies a specific brown adipocyte population of Ucp1-low cells that are pyroptotic and display a reduction in the longevity gene syntaxin 4 (Stx4a). Similar to aged brown adipocytes, Ucp1-STX4KO mice display loss of brown adipose tissue mass and thermogenic dysfunction concomitant with increased pyroptosis. Restoration of STX4 expression or suppression of pyroptosis activation protects against the decline in both mass and thermogenic activity in the aged and Ucp1-STX4KO mice. Mechanistically, STX4 deficiency reduces oxidative phosphorylation, glucose uptake, and glycolysis leading to reduced ATP levels, a known triggering signal for pyroptosis. Together, these data demonstrate an understanding of rapid brown adipocyte involution and that physiologic aging and thermogenic dysfunction result from pyroptotic signaling activation.
Pyruvate kinase M2 (PKM2) is a key player in the Warburg effect of cancer cells. However, the mechanisms of regulating PKM2 are not fully elucidated. Here, we identified the protein-serine/threonine ...kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis, co-activating HIF-1α and β-catenin, and cell proliferation, while enhancing mitochondrial respiration of cancer cells. These findings demonstrate that PIM2-dependent phosphorylation of PKM2 is critical for regulating the Warburg effect in cancer, highlighting PIM2 as a potential therapeutic target.
Background: The protein-serine/threonine kinase PIM2 regulates glycolysis, but the mechanism is not fully elucidated.
Results: PIM2 interacts with PKM2 and phosphorylates PKM2 on the Thr-454 residue.
Conclusion: This phosphorylation of PKM2 increases glycolysis and proliferation in cancer cells.
Significance: PIM2-dependent phosphorylation of PKM2 is critical for regulating the Warburg effect in cancer, highlighting PIM2 as a potential therapeutic target.
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