The AMPK pathway in fatty liver disease

Frontiers in Physiology, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 25, 2022

Lipid metabolism disorders are the primary causes for occurrence and progression of various liver diseases, including non-alcoholic fatty disease (NAFLD) alcoholic (AFLD) caused by a high-fat diet ethanol. AMPK signaling pathway plays an important role in ameliorating lipid disorders. Progressive research has clarified that signal axes involved prevention reduction injury. Upregulation AMK can alleviate FLD mice induced alcohol or insulin resistance, type 2 diabetes, obesity, most natural agonists regulate metabolism, inflammation, oxidative stress hepatocytes, consequently regulating mice. In NAFLD AFLD, increasing activity inhibit synthesis acids cholesterol down-regulating expression adipogenesis gene (FAS, SREBP-1c, ACC HMGCR); Simultaneously, acid oxidation decomposition genes (CPT1, PGC1, HSL, ATGL) decomposition, body’s balance be maintained. At present, some activators thought to beneficial during therapeutic treatment. Therefore, activation is potential target liver. We summarized recent on this review. we performed detailed description each axis pathway, as well discussion its mechanism action significance.

Language: Английский

---

Pathophysiology of obesity and its associated diseases

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 13(6), P. 2403 - 2424

Published: Jan. 13, 2023

The occurrence of obesity has increased across the whole world. Many epidemiological studies have indicated that strongly contributes to development cancer, cardiovascular diseases, type 2 diabetes, liver diseases and other disorders, accounting for a heavy burden on public health-care systems every year. Excess energy uptake induces adipocyte hypertrophy, hyperplasia formation visceral fat in non-adipose tissues evoke disease, diseases. Adipose tissue can also secrete adipokines inflammatory cytokines affect local microenvironment, induce insulin resistance, hyperglycemia, activate associated signaling pathways. This further exacerbates progression obesity-associated Although some progress treatment been achieved preclinical clinical studies, pathogenesis obesity-induced are complex unclear. We still need understand their links better guide In this review, we review between with view improve future management its co-morbidities.

Language: Английский

---

FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases

Frontiers in Endocrinology, Journal Year: 2020, Volume and Issue: 11

Published: Dec. 14, 2020

The rising global prevalence of obesity, metabolic syndrome, and type 2 diabetes has driven a sharp increase in non-alcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation the liver. Approximately one-sixth NAFLD population progresses to steatohepatitis (NASH) with inflammation, hepatocyte injury cell death, fibrosis cirrhosis. NASH is one leading causes transplant, an increasingly common cause hepatocellular carcinoma (HCC), underscoring need for intervention. complex pathophysiology NASH, predicted 3–5% adult worldwide, prompted drug development programs aimed at multiple targets across all stages disease. Currently, there are no approved therapeutics. Liver-related morbidity mortality highest more advanced fibrotic which led early focus on anti-fibrotic approaches prevent progression cirrhosis HCC. Due limited clinical efficacy, have been superseded mechanisms that target underlying driver pathogenesis, namely steatosis, drives downstream inflammation fibrosis. Among this wave therapeutic targeting pathogenesis hormone fibroblast growth factor 21 (FGF21) holds considerable promise; it decreases while suppressing preclinical studies. In review, we summarize data from studies FGF21 analogs, context diseases.

Language: Английский

---

An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(2), P. 552 - 566

Published: April 14, 2023

Language: Английский

---

Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication

Cell Metabolism, Journal Year: 2021, Volume and Issue: 33(8), P. 1685 - 1700.e9

Published: July 7, 2021

Language: Английский

---

Transcriptomics Identify Thrombospondin‐2 as a Biomarker for NASH and Advanced Liver Fibrosis

Hepatology, Journal Year: 2021, Volume and Issue: 74(5), P. 2452 - 2466

Published: June 9, 2021

NAFLD is the most common liver disease worldwide. NASH, progressive form of NAFLD, and advanced fibrosis are associated with poor outcomes. We searched for their noninvasive biomarkers.Global RNA sequencing tissue from 98 patients biopsy-proven was performed. Unsupervised hierarchical clustering well distinguished NASH nonalcoholic fatty (NAFL), exhibited molecular abnormalities reflecting pathological features. Transcriptomic analysis identified proteins up-regulated in and/or (stage F3-F4), including matricellular glycoprotein thrombospondin-2 (TSP-2), encoded by thrombospondin 2 (THBS2) gene. The intrahepatic THBS2 expression level showed highest areas under receiver operating characteristic curves (AUROCs) 0.915 0.957 diagnosing fibrosis, respectively. positively correlated inflammation ballooning according to activity score, serum aspartate aminotransferase hyaluronic acid (HA) levels, Fibrosis Score (NFS). extracellular matrix collagen biosynthesis, platelet activation, caspase-mediated cleavage cytoskeletal proteins, immune cell infiltration. Serum TSP-2 measured 213 significantly higher than NAFL, increased parallel stage. AUROCs predicting were 0.776 0.856, respectively, which comparable Fibrosis-4 index, HA level, NFS diagnosis. count independent predictors fibrosis. levels could stratify risk hepatic complications, cancer decompensated cirrhotic events.TSP-2 may be a useful biomarker diagnosis NAFLD.

Language: Английский

---

Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1

Science, Journal Year: 2022, Volume and Issue: 376(6590)

Published: April 14, 2022

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) remain without effective therapies. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is a potential therapeutic target, but conflicting interpretations have been proposed for how mTORC1 controls lipid homeostasis. We show that selective inhibition signaling in mice, through deletion the RagC/D guanosine triphosphatase-activating protein folliculin (FLCN), promotes activation transcription factor E3 (TFE3) affecting other targets protects against NAFLD NASH. Disease protection mediated by TFE3, which both induces consumption suppresses anabolic lipogenesis. TFE3 inhibits lipogenesis suppressing proteolytic processing sterol regulatory element-binding protein-1c (SREBP-1c) interacting with SREBP-1c on chromatin. Our data reconcile previously studies identify as approach to treat NASH NAFLD.

Language: Английский

---

An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(677)

Published: Jan. 4, 2023

Advanced hepatic fibrosis, driven by the activation of stellate cells (HSCs), affects millions worldwide and is strongest predictor mortality in nonalcoholic steatohepatitis (NASH); however, there are no approved antifibrotic therapies. To identify drug targets, we integrated progressive transcriptomic morphological responses that accompany HSC advanced disease using single-nucleus RNA sequencing tissue clearing a robust murine NASH model. In found an autocrine signaling circuit emerged was composed 68 receptor-ligand interactions conserved between human NASH. These predicted were supported parallel appearance markedly increased direct cell-cell contacts As proof principle, pharmacological inhibition one such interaction, neurotrophic receptor tyrosine kinase 3–neurotrophin 3, inhibited culture reversed fibrosis. summary, uncovered repertoire targets underlying fibrosis vivo. The findings suggest therapeutic paradigm which stage-specific therapies could yield enhanced efficacy patients with

Language: Английский

---

The intersection between alcohol-related liver disease and nonalcoholic fatty liver disease

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 20(12), P. 764 - 783

Published: Aug. 15, 2023

Language: Английский

---

Tumor-Associated Macrophages in Hepatocellular Carcinoma Pathogenesis, Prognosis and Therapy

Cancers, Journal Year: 2022, Volume and Issue: 14(1), P. 226 - 226

Published: Jan. 4, 2022

Hepatocellular carcinoma (HCC) constitutes a major health burden globally, and it is caused by intrinsic genetic mutations acting in concert with multitude of epigenetic extrinsic risk factors. Cancer induces myelopoiesis the bone marrow, as well mobilization hematopoietic stem progenitor cells, which reside spleen. Monocytes produced marrow spleen further infiltrate tumors, where they differentiate into tumor-associated macrophages (TAMs). The relationship between chronic inflammation hepatocarcinogenesis has been thoroughly investigated over past decade; however, several aspects role TAMs HCC development are yet to be determined. In response certain stimuli signaling, monocytes antitumor properties, classified M1-like. On other hand, under different polarization shifts towards an M2-like phenotype tumor promoting capacity. drive growth both directly indirectly, via suppression cytotoxic cell populations, including CD8+ T cells NK cells. microenvironment affects immunotherapies. Therefore, enhanced understanding its immunobiology essential for next-generation utilization various monocyte-centered anticancer treatment modalities clinical investigation, selectively targeting modulating processes monocyte recruitment, activation migration. This review summarizes current evidence on pathogenesis progression, their potential involvement therapy, shedding light emerging methods monocytes.

Language: Английский

---