Immune-related pathogenesis and therapeutic strategies of nonalcoholic steatohepatitis

Chung, Ki Wung; Cho, Ye Eun; Kim, Seung-Jin; Hwang, Seonghwan

doi:10.1007/s12272-022-01379-1

Cited by 4 publications

(4 citation statements)

References 164 publications

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“…When fat influx into hepatocytes surpasses their ability to dispose of it, the ectopic fat deposition damages these hepatocytes through lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, and oxidative stress. [3][4][5] This process occurs in the development of both MASLD and ALD. Furthermore, ethanol and its metabolites damage hepatocytes in the pathogenesis of ALD.…”

Section: Lay Summarymentioning

confidence: 99%

“…6 Additionally, ethanol metabolism via the microsomal ethanol oxidation system produces reactive oxygen species (ROS) that exacerbates lipid peroxidation and depletion of the antioxidant system. 5,7 Although hepatocyte injury is an important factor in the development of MASLD and ALD, their pathogenesis involves more complex processes that occur concomitantly or follow hepatocyte injury. Damaged hepatocytes release damageassociated molecular patterns (DAMPs), which stimulate the innate immune system to induce inflammation in order to maintain tissue homeostasis.…”

Section: Lay Summarymentioning

confidence: 99%

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Role of Neutrophils in the Development of Steatotic Liver Disease

Choi,

Kim,

Hwang

2024

Semin Liver Dis

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This review explores the biological aspects of neutrophils, their contributions to the development of steatotic liver disease, and their potential as therapeutic targets for the disease. Although alcohol-associated and metabolic dysfunction-associated liver diseases originate from distinct etiological factors, the two diseases frequently share excessive lipid accumulation as a common contributor to their pathogenesis, thereby classifying them as types of steatotic liver disease. Dysregulated lipid deposition in the liver induces hepatic injury, triggering the activation of the innate immunity, partially through neutrophil recruitment. Traditionally recognized for their role in microbial clearance, neutrophils have recently garnered attention for their involvement in sterile inflammation, a pivotal component of steatotic liver disease pathogenesis. In conclusion, technological innovations, including single-cell RNA sequencing, have gradually disclosed the existence of various neutrophil subsets; however, how the distinct subsets of neutrophil population contribute differentially to the development of steatotic liver disease remains unclear.

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Section: Lay Summarymentioning

confidence: 99%

Section: Lay Summarymentioning

confidence: 99%

Role of Neutrophils in the Development of Steatotic Liver Disease

Choi,

Kim,

Hwang

2024

Semin Liver Dis

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“…The development of hepatic steatosis is the “first hit”, and sequential or simultaneous combinations of genetic susceptibilities, dietary habits, lifestyle factors, metabolic dysfunction (primarily insulin resistance), and/or alterations in the gut microbiome are all potential contributors to the development of more advanced liver disease [ 23 , 24 ]. Through this pathway, the subsequent or concurrent activation of the adaptive and innate immune system leads to the activation of hepatic stellate cells and Kupffer cells, promoting fibrosis and cirrhosis [ 25 ].…”

Section: Bodymentioning

confidence: 99%

Understanding NAFLD: From Case Identification to Interventions, Outcomes, and Future Perspectives

et al. 2023

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While non-alcoholic fatty liver disease (NAFLD) is a prevalent and frequent cause of liver-related morbidity and mortality, it is also strongly associated with cardiovascular disease-related morbidity and mortality, likely driven by its associations with insulin resistance and other manifestations of metabolic dysregulation. However, few satisfactory pharmacological treatments are available for NAFLD due in part to its complex pathophysiology, and challenges remain in stratifying individual patient’s risk for liver and cardiovascular disease related outcomes. In this review, we describe the development and progression of NAFLD, including its pathophysiology and outcomes. We also describe different tools for identifying patients with NAFLD who are most at risk of liver-related and cardiovascular-related complications, as well as current and emerging treatment options, and future directions for research.

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“…The recent surge in obesity rates has increased the prevalence of fatty liver, which is a hepatic manifestation of metabolic syndrome characterized by the aberrant accumulation of fat in the liver [ 1 , 2 , 3 ]. Approximately 30% of the adult population is affected by fatty liver, which highlights the need to develop appropriate pharmacological interventions [ 4 , 5 , 6 ]. The hepatic fat content is regulated by a combination of four processes: de novo fatty acid synthesis, fatty acid uptake from the circulation, triglyceride secretion mediated by very-low-density lipoprotein, and fatty acid beta-oxidation [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Dimethyloxalylglycine Suppresses SREBP1c and Lipogenic Gene Expressions in Hepatocytes Independently of HIF1A

Kwon,

Cho,

Kim

et al. 2024

CIMB

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Dimethyloxalylglycine (DMOG) is a representative inhibitor of the prolyl hydroxylase domain (PHD), which mediates the degradation of hypoxia-inducible factor-1-alpha (HIF1A). DMOG exerts its pharmacological effects via the canonical pathway that involves PHD inhibition; however, it remains unclear whether DMOG affects lipogenic gene expression in hepatocytes. We aimed to elucidate the effects of DMOG on sterol regulatory element-binding protein-1c (SREBP1c), a master regulator of fatty acid synthesis in hepatocytes. DMOG treatment inhibited SREBP1c mRNA and protein expression in HepG2 and AML12 hepatocytes and reduced the transcript levels of SREBP1c-regulated lipogenic genes. A luciferase reporter assay revealed that DMOG inhibited the transcriptional activity of SREBP1c. Moreover, DMOG suppressed SREBP1c expression in mice liver. Mechanistically, treatment with DMOG enhanced the expression of HIF1A and insulin-induced gene 2 (INSIG2), which inhibits the activation of SREBP1c. However, HIF1A or INSIG2 knockdown failed to reverse the inhibitory effect of DMOG on SREBP1c expression, suggesting a redundant role of HIF1A and INSIG2 in terms of repressing SREBP1c. DMOG did not function through the canonical pathway involving inhibition of SREBP1c by PHD, highlighting the presence of non-canonical pathways that mediate its anti-lipogenic effect.

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Immune-related pathogenesis and therapeutic strategies of nonalcoholic steatohepatitis

Cited by 4 publications

References 164 publications

Role of Neutrophils in the Development of Steatotic Liver Disease

Role of Neutrophils in the Development of Steatotic Liver Disease

Understanding NAFLD: From Case Identification to Interventions, Outcomes, and Future Perspectives

Dimethyloxalylglycine Suppresses SREBP1c and Lipogenic Gene Expressions in Hepatocytes Independently of HIF1A

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