Journal of Genetics and Genomics

Tumor necrosis factor-α signaling in nonalcoholic steatohepatitis and targeted therapies

Sijia Lu, Yibing Wang, Junli Liu

2022, 49(4): 269-278. doi: 10.1016/j.jgg.2021.09.009

Abstract (303) PDF (31)

Abstract:
Nonalcoholic steatohepatitis (NASH), an inflammatory subtype of nonalcoholic fatty liver disease, is featured by significantly elevated levels of various proinflammatory cytokines. Among numerous proinflammatory factors that contribute to NASH pathogenesis, the secreted protein, tumor necrosis factor-alpha (TNF-α), plays an essential role in multiple facets of NASH progression and is therefore considered as a potential therapeutic target. In this review, we will first systematically describe the preclinical studies on the biochemical function of TNF-α and its intracellular downstream signaling mechanisms through its receptors. Moreover, we extensively discuss its functions in regulating inflammation, cell death, and fibrosis of liver cells in the pathogenesis of NASH, and the molecular mechanism that TNF-α expression is regulated by NF-κB and other upstream master regulators during NASH progression. As TNF-α is one of the causal factors that remarkably contributes to NASH progression, combination of therapeutic modalities, including TNF-α-based therapies may lead to the resolution of NASH via multiple pathways and thus generate clinical benefits. For translational studies, we summarize recent advances in strategies targeting TNF-α and its signaling pathway, which paves the way for potential therapeutic treatments for NASH in the future.

Epigenome-Metabolome-Epigenome signaling cascade in cell biological processes

Linpeng Li, Keshi Chen, Yi Wu, Ge Xiang, Xingguo Liu

2022, 49(4): 279-286. doi: 10.1016/j.jgg.2021.09.006

Abstract (385) PDF (37)

Abstract:
Cell fate determination as a fundamental question in cell biology has been extensively studied at different regulatory levels for many years. However, the mechanisms of multilevel regulation of cell fate determination remain unclear. Recently, we have proposed an Epigenome-Metabolome-Epigenome (E-M-E) signaling cascade model to describe the cross-over cooperation during mouse somatic cell reprogramming. In this review, we summarize the broad roles of E-M-E signaling cascade in different cell biological processes, including cell differentiation and dedifferentiation, cell specialization, cell proliferation, and cell pathologic processes. Precise E-M-E signaling cascades are critical in these cell biological processes, and it is of worth to explore each step of E-M-E signaling cascade. E-M-E signaling cascade model sheds light on and may open a window to explore the mechanisms of multilevel regulation of cell biological processes.

Mitochondrial sirtuins, metabolism, and aging

Zhejun Ji, Guang-Hui Liu, Jing Qu

2022, 49(4): 287-298. doi: 10.1016/j.jgg.2021.11.005

Abstract (243) PDF (31)

Abstract:
Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life. Multiple signaling pathways that regulate metabolism also play critical roles in aging, such as PI3K/AKT, mTOR, AMPK, and sirtuins (SIRTs). Among them, sirtuins are known as a protein family with versatile functions, such as metabolic control, epigenetic modification and lifespan extension. Therefore, by understanding how sirtuins regulate metabolic processes, we can start to understand how they slow down or accelerate biological aging from the perspectives of metabolic regulation. Here, we review the biology of SIRT3, SIRT4, and SIRT5, known as the mitochondrial sirtuins due to their localization in the mitochondrial matrix. First, we will discuss canonical pathways that regulate metabolism more broadly and how these are integrated with aging regulation. Then, we will summarize the current knowledge about functional differences between SIRT3, SIRT4, and SIRT5 in metabolic control and integration in signaling networks. Finally, we will discuss how mitochondrial sirtuins regulate processes associated with aging and aging-related diseases.

The mechanisms of nucleotide actions in insulin resistance

Kunpeng Liu, Xiaogao Jin, Xiaoying Zhang, Hongkai Lian, Jianping Ye

2022, 49(4): 299-307. doi: 10.1016/j.jgg.2022.01.006

Abstract (293) PDF (20)

Abstract:
Insulin resistance contributes to metabolic disorders in obesity and type 2 diabetes. In mechanisms of insulin resistance, the roles of glucose, fatty acids, and amino acids have been extensively documented in literature. However, the activities of nucleotides remain to be reviewed comprehensively in the regulation of insulin sensitivity. Nucleotides are well known for their activities in biosynthesis of DNA and RNA as well as their signaling activities in the form of cAMP and cGAMP. Their activities in insulin resistance are dependent on the derivatives and corresponding receptors. ATP and NADH, derivatives of adenosine, inhibit insulin signaling inside cells by downregulation of activities of AMPK and SIRT1, respectively. ATP, ADP and AMP, the well-known energy carriers, regulate cellular responses to insulin outside cells through the purinergic receptors in cell surface. Current evidence suggests that ATP, NADH, cGAMP, and uridine are potential biomarkers of insulin resistance. However, GTP and cGMP are likely the markers of insulin sensitization. Here, studies crossing the biomedical fields are reviewed to characterize nucleotide activities in the regulation of insulin sensitivity. The knowledge brings new insights into the mechanisms of insulin resistance.

The composition, function, and regulation of adipose stem and progenitor cells

Xiyan Liao, Haiyan Zhou, Tuo Deng

2022, 49(4): 308-315. doi: 10.1016/j.jgg.2022.02.014

Abstract (296) PDF (46)

Abstract:
White adipose tissue (WAT) is a highly plastic organ that plays a central role in regulating whole-body energy metabolism. Adipose stem and progenitor cells (ASPCs) are essential components of the stromal vascular fraction (SVF) of adipose tissue. They give rise to mature adipocytes and play a critical role in maintaining adipose tissue function. However, the molecular heterogeneity and functional diversity of ASPCs are still poorly understood. Recently, single-cell RNA sequencing (scRNA-seq) analysis has identified distinct subtypes of ASPCs in murine and human adipose tissues, providing new insights into the cellular complexity of ASPCs among multiple fat depots. This review summarizes the current knowledge on ASPC populations, including their markers, functions, and regulatory mechanisms. Targeting one or several of these cell populations may ameliorate metabolic disorders by promoting adaptive hyperplastic adipose growth.

Transcriptional control of pancreatic β-cell identity and plasticity during the pathogenesis of type 2 diabetes

Ziyin Zhang, Yue Gao, Zhuo-Xian Meng

2022, 49(4): 316-328. doi: 10.1016/j.jgg.2022.03.002

Abstract (156) PDF (16)

Abstract:
Type 2 diabetes (T2D) is caused by insulin resistance and insufficient insulin secretion. Evidence has increasingly indicated that pancreatic β-cell dysfunction is the primary determinant of T2D disease progression and remission. High plasticity is an important feature of pancreatic β-cells. During T2D development, pancreatic β-cells undergo dynamic adaptation. Although β-cell death/apoptosis in later-stage T2D is the major cause of β-cell dysfunction, recent studies have revealed that β-cell dedifferentiation and reprogramming, which play critical roles in β-cell functional regulation in the early and middle T2D progression stages, are characterized by (i) a loss of mature β-cell-enriched genes; (ii) dedifferentiation to a progenitor-like state; and (iii) transdifferentiation into other cell types. The roles of transcription factors (TFs) in the establishment and maintenance of β-cell identity during pancreatic development have been extensively studied. Here, we summarize the roles and underlying mechanisms of TFs in the maintenance of β-cell identity under physiological and type 2 diabetic conditions. Several feasible approaches for restoring islet functions are also discussed. A better understanding of the transcriptional control of β-cell identity and plasticity will pave the way for developing more effective strategies, such as β-cell regeneration therapy, to treat T2D and associated metabolic disorders.

Effect of disrupted episodic memory on food consumption: no impact of neuronal loss of endophilin A1 on food intake and energy balance

Jacques Togo, Yanrui Yang, Sumei Hu, Jia-Jia Liu, John R. Speakman

2022, 49(4): 329-337. doi: 10.1016/j.jgg.2022.01.005

Abstract (197) PDF (9)

Abstract:
Food intake is generally assumed to reflect a regulatory tension between homeostatic and hedonic drivers. Information from individuals with memory dysfunction suggests that episodic memory may also play a significant role. We reasoned that if memory influences food intake, then disrupting a genetic factor that is important in episodic memory formation should affect food intake and energy balance. We performed spatial learning tests on neuronal specific endophilin A1 (EENA1) KO mice using the four-arm baited version of the radial arms maze (RAM). Energy regulation has also been evaluated. As anticipated neuronal EENA1 KO mice had impaired spatial memory. However, loss of endophilin A1 did not result in greater food intake, or altered energy absorption efficiency, relative to wild-type (WT) mice, when fed either low or high fat diets. Moreover, loss of EENA1 did not significantly affect other features of energy balance—physical activity and energy expenditure. No statistically significant changes were observed in the expression of hypothalamic neuropeptides related to food intake regulation, or circulating levels of leptin. We conclude that food intake and energy balance are largely governed by homeostatic and hedonic processes, and when these processes are intact memory probably plays a relatively minor role in food intake regulation.

The S100 calcium binding protein A11 promotes liver fibrogenesis by targeting TGF-β signaling

Tingting Zhu, Linqiang Zhang, Chengbin Li, Xiaoqiong Tan, Jing Liu, Huiqin Li, Qijing Fan, Zhiguo Zhang, Mingfeng Zhan, Lin Fu, Jinbo Luo, Jiawei Geng, Yingjie Wu, Xiaoju Zou, Bin Liang

2022, 49(4): 338-349. doi: 10.1016/j.jgg.2022.02.013

Abstract (140) PDF (17)

Abstract:
Liver fibrosis is a key transformation stage and also a reversible pathological process in various types of chronic liver diseases. However, the pathogenesis of liver fibrosis still remains elusive. Here, we report that the calcium binding protein A11 (S100A11) is consistently upregulated in the integrated data from GSE liver fibrosis and tree shrew liver proteomics. S100A11 is also experimentally activated in liver fibrosis in mouse, rat, tree shrew, and human with liver fibrosis. While overexpression of S100A11 in vivo and in vitro exacerbates liver fibrosis, the inhibition of S100A11 improves liver fibrosis. Mechanistically, S100A11 activates hepatic stellate cells (HSCs) and the fibrogenesis process via the regulation of the deacetylation of Smad3 in the TGF-β signaling pathway. S100A11 physically interacts with SIRT6, a deacetylase of Smad2/3, which may competitively inhibit the interaction between SIRT6 and Smad2/3. The subsequent release and activation of Smad2/3 promote the activation of HSCs and fibrogenesis. Additionally, a significant elevation of S100A11 in serum is observed in clinical patients. Our study uncovers S100A11 as a novel profibrogenic factor in liver fibrosis, which may represent both a potential biomarker and a promising therapy target for treating liver fibrosis and fibrosis-related liver diseases.

Human HAND1 inhibits the conversion of cholesterol to steroids in trophoblasts

Haibin Zhu, Qianlei Ren, Ziyi Yan, Shouying Xu, Jiahao Luo, Ximei Wu, Chao Tang

2022, 49(4): 350-363. doi: 10.1016/j.jgg.2021.07.014

Abstract (113) PDF (16)

Abstract:
Steroidogenesis from cholesterol in placental trophoblasts is fundamentally involved in the establishment and maintenance of pregnancy. The transcription factor gene heart and neural crest derivatives expressed 1 (Hand1) promotes differentiation of mouse trophoblast giant cells. However, the role of HAND1 in human trophoblasts remains unknown. Here, we report that HAND1 inhibits human trophoblastic progesterone (P4) and estradiol (E2) from cholesterol through downregulation of the expression of steroidogenic enzymes, including aromatase, P450 cholesterol side-chain cleavage enzyme (P450scc), and 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1). Mechanically, although HAND1 inhibits transcription of aromatase by directly binding to aromatase gene promoter, it restrains transcription of P450scc by upregulation of the methylation status of P450scc gene promoter through its binding to ALKBH1, a demethylase. Unlike aromatase and P450scc, HAND1 decreases 3β-HSD1 mRNA levels by the reduction of its RNA stability through binding to and subsequent destabilizing protein HuR. Finally, HAND1 suppresses circulating P4 and E2 levels derived from JEG-3 xenograft and attenuates uterine response to P4 and E2. Thus, our results uncover a hitherto uncharacterized role of HAND1 in the regulation of cholesterol metabolism in human trophoblasts, which may help pinpoint the underlying mechanisms involved in supporting the development and physiological function of the human placenta.

Functionalized gadofullerene ameliorates impaired glycolipid metabolism in type 2 diabetic mice

Jin Wu, Yingbo Chen, Xue Li, Liyuan Ran, Xiangdong Liu, Xiaoshuang Wang, Mingming Zhen, Shanshan Shao, Li Zeng, Chunru Wang, Bin Liang, Jiajun Zhao, Yingjie Wu

2022, 49(4): 364-376. doi: 10.1016/j.jgg.2021.09.004

Abstract (281) PDF (58)

Abstract:
The soaring global prevalence of diabetes makes it urgent to explore new drugs with high efficacy and safety. Nanomaterial-derived bioactive agents are emerging as one of the most promising candidates for biomedical application. In the present study, we investigated the anti-diabetic effects of a functionalized gadofullerene (GF) using obese db/db and non-obese mouse model of type 2 diabete mellitus (MKR) mouse type 2 diabetes mellitus (T2DM) models. In both mouse models, the diabetic phenotypes, including hyperglycemia, impaired glucose tolerance, and insulin sensitivity, were ameliorated after two or four weeks of intraperitoneal administration of GF. GF lowered blood glucose levels in a dose-dependent manner. Importantly, the restored blood glucose levels could persist ten days after withdrawal of GF treatment. The hepatic AKT/GSK3β/FoxO1 pathway is shown to be the main target of GF for rebalancing gluconeogenesis and glycogen synthesis in vivo and in vitro. Furthermore, GF treatment significantly reduced weight gain of db/db mice with reduced hepatic fat storage by the inhibition of de novo lipogenesis through mTOR/S6K/SREBP1 pathway. Our data provide compelling evidence to support the promising application of GF for the treatment of T2DM.

BAP60 plays an opposite role to the MRT-NURF complex in regulating lipid droplet size

Yan Yao, Mengyao Xu, Lianyong Qiao, Hu Nie, Falong Lu, Xun Huang

2022, 49(4): 377-379. doi: 10.1016/j.jgg.2022.02.003

Abstract (245) PDF (36)

Abstract:

Targeted lipidomics reveals plasmalogen phosphatidylethanolamines and storage triacylglycerols as the major systemic lipid aberrations in Bietti crystalline corneoretinal dystrophy

Shijing Wu, Sin Man Lam, Huajin Li, Binhua Jiang, Zixi Sun, Tian Zhu, Xing Wei, Xuan Zou, Guanghou Shui, Ruifang Sui

2022, 49(4): 380-383. doi: 10.1016/j.jgg.2021.10.003

Abstract (223) PDF (33)

Abstract:

2022 Vol. 49, No. 4