Background: Metabolic-associated steatohepatitis (MASH) is one of the most prevalent liver diseases worldwide, with a global prevalence estimated between 3% and 5%, posing a significant health burden. Human liver organoids (HLOs) have previously been generated to model steatohepatitis, offering a potential cellular disease model for studying MASH. However, the current HLO model lacks detailed molecular characterizations and requires further improvement.
View Article and Find Full Text PDFBackground: Metabolic dysfunction-associated fatty liver disease (MAFLD) affects up to one-third of the global population. Since no approved pharmacotherapy for MAFLD is available, lifestyle modification remains the cornerstone of clinical care. Our study aims to evaluate the association of an overall healthy lifestyle with MAFLD risk.
View Article and Find Full Text PDFMORF4 (mortality factor on chromosome 4)-related gene 15 (MRG15) is a chromodomain protein that exists in various multiprotein complexes involved in transcription, DNA repair, and development. Here we summarize the recent advances involving MRG15 in modulating liver metabolism, both through its chromatin-binding capability and independently of it, highlighting MRG15 as a potential therapeutic target for liver metabolic diseases.
View Article and Find Full Text PDFHepatic insulin resistance is central to the metabolic syndrome. Here we investigate the role of BTB and CNC homology 1 (BACH1) in hepatic insulin signaling. BACH1 is elevated in the hepatocytes of individuals with obesity and patients with non-alcoholic fatty liver disease (NAFLD).
View Article and Find Full Text PDFAging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need.
View Article and Find Full Text PDFThe early phase lipid accumulation is essential for liver regeneration. However, whether this acute lipid accumulation can serve as signals to direct liver regeneration rather than simply providing building blocks for cell proliferation remains unclear. Through in vivo CRISPR screening, we identify MIER1 (mesoderm induction early response 1) as a key epigenetic regulator that bridges the acute lipid accumulation and cell cycle gene expression during liver regeneration in male animals.
View Article and Find Full Text PDFPreclinical models that can accurately predict the toxicity and efficacy of candidate drugs to human liver tissue are in urgent need. Human liver organoid (HLO) derived from human pluripotent stem cells offers a possible solution. Herein, we generated HLOs, and demonstrated the utility of these HLOs in modeling a diversity of phenotypes associated with drug-induced liver injury (DILI), including steatosis, fibrosis, and immune responses.
View Article and Find Full Text PDFThe glucagon-PKA signal is generally believed to control hepatic gluconeogenesis via the CREB transcription factor. Here we uncovered a distinct function of this signal in directly stimulating histone phosphorylation for gluconeogenic gene regulation in mice. In the fasting state, CREB recruited activated PKA to regions near gluconeogenic genes, where PKA phosphorylated histone H3 serine 28 (H3S28ph).
View Article and Find Full Text PDFAdipose tissue loss seen with cancer-associated cachexia (CAC) may functionally drive cachexia development. Using single-cell transcriptomics, we unveil a large-scale comprehensive cellular census of the stromal vascular fraction of white adipose tissues from patients with or without CAC. We report depot- and disease-specific clusters and developmental trajectories of adipose progenitors and immune cells.
View Article and Find Full Text PDFAlthough disrupted bile acid (BA) homeostasis is implicated in inflammatory bowel disease (IBD), the role of hepatic BA metabolism in the pathogenesis of colitis is poorly understood. Here, we found that cholic acid (CA) levels were increased in patients and mice. Cytochrome P450 8B1 (CYP8B1), which synthesizes CA, was induced in livers of colitic mice.
View Article and Find Full Text PDFBackground & Aims: How hepatic steatosis progresses to non-alcoholic steatohepatitis (NASH) is complicated and remains unclear. The mortality factor 4-like protein 1 (MORF4L1, also called MRG15) was previously identified as a master nuclear chromatin remodeler in the rhythmic regulation of lipid synthesis gene expression in the liver. Whether it also contributes to the progression from liver steatosis to NASH is unclear.
View Article and Find Full Text PDFBackground: Esophageal Squamous Cell Carcinoma (ESCC) was characterized as a regional-prevalent and aggressive tumor with high morbidity and mortality. NIMA-related kinase 2 (NEK2) is an interesting oncogene, the alteration of which leads to patients-beneficial outcomes. We aimed to explore the role of NEK2 in ESCC and excavate its mechanism.
View Article and Find Full Text PDFPurpose: Viral keratitis caused by herpes simplex virus 1 (HSV-1) is a lifelong recurring disease and an unignored cause of blindness worldwide. Current antiviral therapy cannot eliminate the transcriptionally silent HSV-1 in latently infected patients. With the explosive applications of the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease (Cas) 9 gene-editing system in recent years, we aim to develop a CRISPR/Cas9 system targeting down the major HSV receptor, NECTIN-1 on human corneal epithelial cells (HCECs), to provide a novel strategy for herpes simplex keratitis (HSK) treatment.
View Article and Find Full Text PDFWe provide a protocol for gene editing in mouse hepatocytes using the CRISPR-Cas9 technology via AAV delivery. This protocol describes the construction of AAV plasmids, AAV packaging, injection, and the detection of knockout efficiency. Using this protocol, we can get up to 10 AAV and knock out genes in hepatocytes efficiently within 15 days.
View Article and Find Full Text PDFThe mechanisms underlying the pathogenesis of steatosis and insulin resistance in nonalcoholic fatty liver disease remain elusive. Increased phosphorylation of hepatic p38 has long been noticed in fatty liver; however, whether the activation of hepatic p38 is a cause or consequence of liver steatosis is unclear. Here, we demonstrate that hepatic p38 activation by MKK6 overexpression in the liver of mice induces severe liver steatosis, reduces fat mass, and elevates circulating fatty acid levels in a hepatic p38α- and FGF21-dependent manner.
View Article and Find Full Text PDFSheng Li Xue Bao
October 2021
The high failure rate of the new drug development has been well recognized. Relying on the pre-clinical data obtained from animal experiments will inevitably cause a low concordance with human clinical trials, which will eventually lead to new drug development failure. Employing human induced pluripotent stem cells (iPSCs) or adult stem cells to simulate disease models can not only provide an unlimited cell materials, but also faithfully represent the genetic background of a certain disease, when iPSCs or adult stem cells derived from patients with a specific disease genetic variation are applied.
View Article and Find Full Text PDFThe mechanisms underlying the pathogenesis of steatosis and insulin resistance in nonalcoholic fatty liver disease remain elusive. Increased phosphorylation of hepatic p38 has long been noticed in fatty liver; however, whether the activation of hepatic p38 is a cause or consequence of liver steatosis is unclear. Here, we demonstrate that hepatic p38 activation by MKK6 overexpression in the liver of mice induces severe liver steatosis, reduces fat mass, and elevates circulating fatty acid levels in a hepatic p38α- and FGF21-dependent manner.
View Article and Find Full Text PDFHuman pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have great value for studies of human cardiac development, drug discovery, disease modeling, and cell therapy. However, the mixed cardiomyocyte subtypes (ventricular-, atrial-, and nodal-like myocytes) and the maturation heterogeneity of hPSC-CMs restrain their application in vitro and in vivo. Myosin light chain 2 (MYL2, encoding the ventricular/cardiac muscle isoform MLC2v protein) is regarded as a ventricular-specific marker of cardiac myocardium; however, its restricted localization to ventricles during human heart development has been questioned.
View Article and Find Full Text PDFAn improved understanding of thyroid hormone (TH) action on cholesterol metabolism will facilitate the identification of novel therapeutic targets for hypercholesterolemia. TH-regulated microRNAs (miRNAs) have been implicated in TH-controlled biological processes; however, whether and how TH-regulated miRNAs mediate the cholesterol-lowering effect of TH remains unclear. Our aim was to identify TH-regulated microRNAs that have cholesterol-lowering effects and explore the underlying mechanism.
View Article and Find Full Text PDFA better understanding of the molecular mechanisms that control the UCP1 expression in brown and beige adipocytes is essential for us to modulate adipose cell fate and promote thermogenesis, which may provide a therapeutic view for the treatment of obesity and obesity-related diseases. To systematically identify -element(s) that transcriptionally regulates we here took advantage of the high-throughput CRIPSR-Cas9 screening system, and performed an saturating mutagenesis screen, by using a customized sgRNA library targeting the ~ 20 kb genomic region near . Through the screening, we have identified several genomic loci that may contain key regulatory element for expression in cultured brown and white adipocytes , and in inguinal white adipose tissue .
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