Mechanism and Therapeutic Targets of c-Jun-N-Terminal Kinases Activation in Nonalcoholic Fatty Liver Disease

Min, Robert Win Maw; Aung, Filbert W.M.; Liu, Bryant; Arya, Aliza; Win, Sanda

doi:10.3390/biomedicines10082035

Cited by 15 publications

(13 citation statements)

References 161 publications

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“…Since NF-κB and AP-1 pathways regulate the expression of pro-inflammatory cytokines, these findings suggest that PPARα may exert its anti-inflammatory effects by suppressing these pathways in the liver. Previous studies reported that saturated fatty acids activate JNK in hepatocytes (50,51), whereas the hepatic JNK is required for AP-1 activation and NCOR1 expression (52). As NCOR1 is a potent co-repressor for PPARα, these findings suggest that the JNK-NCOR1 axis reciprocally affects the PPARα anti-inflammatory effect.…”

Section: Trans-acting Repressionmentioning

confidence: 77%

Mechanistic insights into the peroxisome proliferator-activated receptor alpha as a transcriptional suppressor

Yagai

Nakamura

2022

Front. Med.

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Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent hepatic disorders that 20-30% of the world population suffers from. The feature of NAFLD is excess lipid accumulation in the liver, exacerbating multiple metabolic syndromes such as hyperlipidemia, hypercholesterolemia, hypertension, and type 2 diabetes. Approximately 20-30% of NAFLD cases progress to more severe chronic hepatitis, known as non-alcoholic steatohepatitis (NASH), showing deterioration of hepatic functions and liver fibrosis followed by cirrhosis and cancer. Previous studies uncovered that several metabolic regulators had roles in disease progression as key factors. Peroxisome proliferator-activated receptor alpha (PPARα) has been identified as one of the main players in hepatic lipid homeostasis. PPARα is abundantly expressed in hepatocytes, and is a ligand-dependent nuclear receptor belonging to the NR1C nuclear receptor subfamily, orchestrating lipid/glucose metabolism, inflammation, cell proliferation, and carcinogenesis. PPARα agonists are expected to be novel prescription drugs for NASH treatment, and some of them (e.g., Lanifibranor) are currently under clinical trials. These potential novel drugs are developed based on the knowledge of PPARα-activating target genes related to NAFLD and NASH. Intriguingly, PPARα is known to suppress the expression of subsets of target genes under agonist treatment; however, the mechanisms of PPARα-mediated gene suppression and functions of these genes are not well understood. In this review, we summarize and discuss the mechanisms of target gene repression by PPARα and the roles of repressed target genes on hepatic lipid metabolism, fibrosis and carcinogenesis related to NALFD and NASH, and provide future perspectives for PPARα pharmaceutical potentials.

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Section: Trans-acting Repressionmentioning

confidence: 77%

Mechanistic insights into the peroxisome proliferator-activated receptor alpha as a transcriptional suppressor

Yagai

Nakamura

2022

Front. Med.

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“…Consequently, the heightened activation of the metabolic stress-induced MAPK cascade in hepatocytes causes significant damage to the liver. This process involves upstream MAPK kinases (MAP3K), including apoptosis signal-regulating kinase 1 (ASK1), mixed-lineage kinases (MLKs), TAK1, MAPK kinases (MAP2K) such as mitogen-activated protein kinase kinase 4 (MKK4), MKK7, and terminal stress kinases like JNK and p38 [63,64]. Moreover, serving as an inflammatory pathway associated with various chemical mediators, MAPK activation can impact other bodily systems, including the cardiovascular system.…”

Section: Biochemical and Cellular Patterns Of Mafldmentioning

confidence: 99%

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

De Cól,

de Lima,

Pompeu

et al. 2024

IJMS

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Metabolic-associated fatty liver disease (MAFLD) includes several metabolic dysfunctions caused by dysregulation in the brain–gut–liver axis and, consequently, increases cardiovascular risks and fatty liver dysfunction. In MAFLD, type 2 diabetes mellitus, obesity, and metabolic syndrome are frequently present; these conditions are related to liver lipogenesis and systemic inflammation. This study aimed to review the connection between the brain–gut–liver axis and MAFLD. The inflammatory process, cellular alterations in hepatocytes and stellate cells, hypercaloric diet, and sedentarism aggravate the prognosis of patients with MAFLD. Thus, to understand the modulation of the physiopathology of MAFLD, it is necessary to include the organokines involved in this process (adipokines, myokines, osteokines, and hepatokines) and their clinical relevance to project future perspectives of this condition and bring to light new possibilities in therapeutic approaches. Adipokines are responsible for the activation of distinct cellular signaling in different tissues, such as insulin and pro-inflammatory cytokines, which is important for balancing substances to avoid MAFLD and its progression. Myokines improve the quantity and quality of adipose tissues, contributing to avoiding the development of MAFLD. Finally, hepatokines are decisive in improving or not improving the progression of this disease through the regulation of pro-inflammatory and anti-inflammatory organokines.

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“…Additionally, ASK1 is a MAP3 kinase that activates the downstream terminal kinases, JNK and p38. The ASK1 inhibitor, GS-444217, ameliorated NASH and improved fibrosis in preclinical studies and a short-term clinical trial [ 126 ]; however, this inhibitor was not effective in late-phase clinical trials [ 127 , 128 ]. Currently, biologics and the transplantation of stem cells have been shown to inhibit JNK in DILI through modulation of GSH resynthesis [ 129 ].…”

Section: Pathways For the Treatment Of A Drug-induced Liver Injurymentioning

confidence: 99%

Endoplasmic Reticulum Stress and Mitochondrial Stress in Drug-Induced Liver Injury

Pan

Zhang

et al. 2023

Molecules

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Drug-induced liver injury (DILI) is a widespread and harmful disease closely linked to mitochondrial and endoplasmic reticulum stress (ERS). Globally, severe drug-induced hepatitis, cirrhosis, and liver cancer are the primary causes of liver-related morbidity and mortality. A hallmark of DILI is ERS and changes in mitochondrial morphology and function, which increase the production of reactive oxygen species (ROS) in a vicious cycle of mutually reinforcing stress responses. Several pathways are maladapted to maintain homeostasis during DILI. Here, we discuss the processes of liver injury caused by several types of drugs that induce hepatocyte stress, focusing primarily on DILI by ERS and mitochondrial stress. Importantly, both ERS and mitochondrial stress are mediated by the overproduction of ROS, destruction of Ca2+ homeostasis, and unfolded protein response (UPR). Additionally, we review new pathways and potential pharmacological targets for DILI to highlight new possibilities for DILI treatment and mitigation.

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Mechanism and Therapeutic Targets of c-Jun-N-Terminal Kinases Activation in Nonalcoholic Fatty Liver Disease

Cited by 15 publications

References 161 publications

Mechanistic insights into the peroxisome proliferator-activated receptor alpha as a transcriptional suppressor

Mechanistic insights into the peroxisome proliferator-activated receptor alpha as a transcriptional suppressor

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

Endoplasmic Reticulum Stress and Mitochondrial Stress in Drug-Induced Liver Injury

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