Intermittent Protein Diets Alter Hepatic Lipid Accumulation by Changing Tryptophan Metabolism in a Fast-Response Manner DOI
Xiao-Hui Li, Kai Shan, Chunbao Li

et al.

Journal of Agricultural and Food Chemistry, Journal Year: 2023, Volume and Issue: 71(7), P. 3261 - 3272

Published: Jan. 12, 2023

In modern life, the fluctuation of dietary protein levels is common, in particular, for low-income populations. However, its effect on human health little known. Alternating changes low and high casein or pork were used to simulate content mice. Hepatic lipid accumulation showed a fast response alternating low- high-protein diets. Correspondingly, some gut microbiota tryptophan metabolite composition also changes. The 3-hydroxykynurenine (3-HK) was proven inhibit hepatic vitro. Therefore, intermittent diets modulated through 3-HK. These findings highlighted sensitivity levels.

Language: Английский

Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies DOI Creative Commons
Xiumei Wu, Mengyun Xu,

M. Geng

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 27, 2023

The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. most common form NCD is metabolic diseases, which affect people all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding the will generate novel targets for improved therapies across spectrum. Protein posttranslational modification (PTM) an important term that refers to biochemical specific amino acid residues in target proteins, immensely increases functional diversity proteome. range PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, several PTMs. Here, we offer review roles pathological consequences, including diabetes, obesity, fatty liver hyperlipidemia, atherosclerosis. Building upon this framework, afford description proteins pathways involved by focusing on PTM-based protein modifications, showcase pharmaceutical intervention preclinical studies clinical trials, future perspectives. Fundamental research defining mechanisms whereby regulate open new avenues therapeutic intervention.

Language: Английский

Citations

98
How the ends signal the end: Regulation by E3 ubiquitin ligases recognizing protein termini DOI Creative Commons
Dawafuti Sherpa, Jakub Chrustowicz, Brenda A. Schulman

et al.

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(8), P. 1424 - 1438

Published: March 4, 2022

Specificity of eukaryotic protein degradation is determined by E3 ubiquitin ligases and their selective binding to motifs, termed "degrons," in substrates for ubiquitin-mediated proteolysis. From the discovery first substrate degron corresponding a flurry recent studies enabled modern systems structural methods, it clear that many regulatory pathways depend on E3s recognizing termini. Here, we review basis recognition termini how this underlies biological regulation. Diverse evolved harness substrate's N and/or C terminus (and often adjacent residues as well) sequence-specific manner. Regulation achieved through activation also generation degrons at ribosomes or posttranslational means. Collectively, interactions with enable intricate control quality responses cellular signals.

Language: Английский

Citations

69
Parallel CRISPR-Cas9 screens identify mechanisms of PLIN2 and lipid droplet regulation DOI Creative Commons

Melissa A. Roberts,

Kirandeep K. Deol,

Alyssa J. Mathiowetz

et al.

Developmental Cell, Journal Year: 2023, Volume and Issue: 58(18), P. 1782 - 1800.e10

Published: July 25, 2023

Despite the key roles of perilipin-2 (PLIN2) in governing lipid droplet (LD) metabolism, mechanisms that regulate PLIN2 levels remain incompletely understood. Here, we leverage a set genome-edited human reporter cell lines series CRISPR-Cas9 loss-of-function screens, identifying genetic modifiers influence expression and post-translational stability under different metabolic conditions types. These regulators include canonical genes control metabolism as well involved ubiquitination, transcription, mitochondrial function. We further demonstrate role for E3 ligase MARCH6 regulating triacylglycerol biosynthesis, thereby influencing LD abundance stability. Finally, our CRISPR screens several published provide foundation CRISPRlipid (http://crisprlipid.org), an online data commons lipid-related functional genomics data. Our study identifies regulation provides extensive resource exploration biology metabolism.

Language: Английский

Citations

30
Dietary L-Glu sensing by enteroendocrine cells adjusts food intake via modulating gut PYY/NPF secretion DOI Creative Commons
J. Gao, Song Zhang, Pan Deng

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 25, 2024

Abstract Amino acid availability is monitored by animals to adapt their nutritional environment. Beyond gustatory receptors and systemic amino sensors, enteroendocrine cells (EECs) are believed directly percept dietary acids secrete regulatory peptides. However, the cellular machinery underlying acid-sensing EECs how EEC-derived hormones modulate feeding behavior remain elusive. Here, developing tools specifically manipulate EECs, we find that Drosophila neuropeptide F (NPF) from mated female inhibits feeding, similar human PYY. Mechanistically, L-Glutamate acts through metabotropic glutamate receptor mGluR decelerate calcium oscillations in thereby causing reduced NPF secretion via dense-core vesicles. Furthermore, two dopaminergic enteric neurons expressing NPFR perceive relay an anorexigenic signal brain. Thus, our findings provide mechanistic insights into assess food quality identify a conserved mode of action explains gut NPF/PYY modulates intake.

Language: Английский

Citations

10
Reprograming of the ubiquitin ligase Ubr1 by intrinsically disordered Roq1 through cooperating multifunctional motifs DOI Creative Commons
Niklas Peters,

Sibylle Kanngießer,

Oliver Pajonk

et al.

The EMBO Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Language: Английский

Citations

1
The emerging role of E3 ubiquitin ligases and deubiquitinases in metabolic dysfunction-associated steatotic liver disease DOI Creative Commons
Yu Zhang, Jiahui Yang, Jiali Min

et al.

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 25, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic worldwide, with a prevalence as high 32.4%. MASLD encompasses spectrum of pathologies, ranging from steatosis to metabolic steatohepatitis (MASH), fibrosis, and, in some cases, progression end-stage (cirrhosis and hepatocellular carcinoma). A comprehensive understanding pathogenesis this highly prevalent may facilitate identification novel targets for development improved therapies. E3 ubiquitin ligases deubiquitinases (DUBs) are key regulatory components ubiquitin‒proteasome system (UPS), which plays pivotal role maintaining intracellular protein homeostasis. Emerging evidence implicates that aberrant expression DUBs involved MASLD. Here, we review abnormalities by (1) discussing their targets, mechanisms, functions MASLD; (2) summarizing pharmacological interventions targeting these enzymes preclinical clinical studies; (3) addressing challenges future therapeutic strategies. This synthesizes current highlight strategies based on UPS progressive disease.

Language: Английский

Citations

1
Lingguizhugan decoction improves non-alcoholic steatohepatitis partially by modulating gut microbiota and correlated metabolites DOI Creative Commons

Mingzhe Zhu,

Xue Wang, Kai Wang

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 26, 2023

Background Lingguizhugan decoction is a traditional Chinese medicine prescription that has been used to improve non-alcoholic fatty liver disease and its progressive form, steatohepatitis (NASH). However, the anti-NASH effects underlying mechanisms of remain unclear. Methods Male Sprague-Dawley rats were fed methionine- choline-deficient (MCD) diet induce NASH, then given orally for four weeks. NASH indexes evaluated by histopathological analysis biochemical parameters including serum alanine aminotransferase (ALT), aspartate (AST), triglycerides (TG), etc. Fecal samples subjected profile changes gut microbiota metabolites using 16S rRNA sequencing ultra-performance liquid chromatography coupled tandem mass spectrometry (UPLC-MS). Bioinformatics was identify reversed candidates, Spearman’s correlation performed uncover relationship among microbiota, fecal metabolites, indexes. Results Four-week treatment ameliorated MCD diet-induced features, as evidenced improved hepatic steatosis inflammation, well decreased AST ALT levels. Besides, partially restored in microbial community composition rats. Meanwhile, relative abundance 26 genera significantly changed rats, 11 (such odoribacter, Ruminococcus_1 , Ruminococcaceae_UCG-004, ) identified decoction. Additionally, total 99 altered 57 TDCA, Glutamic acid, Isocaproic enriched different pathways Furthermore, analyses revealed most correlated with Conclusion may exert protective on modulating metabolites.

Language: Английский

Citations

19
The Different Mechanisms of Lipid Accumulation in Hepatocytes Induced by Oleic Acid/Palmitic Acid and High-Fat Diet DOI Creative Commons
Miao Zhang, Xue Bai, Qian Du

et al.

Molecules, Journal Year: 2023, Volume and Issue: 28(18), P. 6714 - 6714

Published: Sept. 20, 2023

Non-alcoholic fatty liver disease (NAFLD) is the primary chronic worldwide, mainly manifested by hepatic steatosis. Hepatic lipids may be derived from dietary intake, plasma free acid (FFA) uptake, or de novo lipogenesis (DNL). Currently, cellular and animal models of hepatocellular steatosis are widely used to study pathogenesis NAFLD investigate therapeutic agents. However, whether there differences between in vivo vitro mechanisms that cause lipid accumulation has not been reported. We OA/PA-induced NCTC 1469 cells high-fat-diet-fed C57BL/6J mice simulate a hepatocyte model detect indicators related FFA uptake DNL. In addition, when serological were analysed mouse model, it was found serum FASN levels decreased. The results revealed that, DNL decreased, enzyme activity unchanged, increased, including high expression CD36; while, both synthesis CD36 increased protein with enhanced activity. after an analysis reduced. conclusion, can mechanism whereas high-fat-diet-induced Combined treatment more effective against NAFLD. as one for clinical diagnosis

Language: Английский

Citations

18
Molecular mechanism and therapeutic significance of essential amino acids in metabolically associated fatty liver disease DOI

Yuting Deng,

Mengsi Hu,

Shufang Huang

et al.

The Journal of Nutritional Biochemistry, Journal Year: 2024, Volume and Issue: 126, P. 109581 - 109581

Published: Jan. 13, 2024

Language: Английский

Citations

8
Essentiality of SLC7A11-mediated nonessential amino acids in MASLD DOI Creative Commons
Jie Shen, Enjun Xie, Shuying Shen

et al.

Science Bulletin, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

Citations

6