Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis

Wang, Qi; Zhou, Haoming; Bu, Qingfa; Wei, Song; Li, Lei; Zhou, Jiang; Zhou, Shun; Su, Wantong; Mu, Lan; Liu, Zheng; Wang, Mingming; Lü, Ling

doi:10.1016/j.jhep.2022.02.031

Cited by 81 publications

(58 citation statements)

References 44 publications

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“…Although IRE1α is protective, it blocks basal levels of UPR in the liver, which may lead to increased ER stress ( 14 ). XBP1 expression is significantly upregulated in liver samples from patients with NASH, and inhibition of the XBP1 signal significantly reduced serum triglyceride, cholesterol and fatty acid levels by reducing the metabolism of liver lipogenesis in mice ( 33 ). Inhibition of the IRE1α pathway in HSC can reduce both their activation and autophagic activity, resulting in a reduced fibrogenic response ( 34 ).…”

Section: The Unfolded Protein Responsementioning

confidence: 99%

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Endoplasmic reticulum stress in innate immune cells - a significant contribution to non-alcoholic fatty liver disease

Zhou

Shen²,

Li³

et al. 2022

Front. Immunol.

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Liver disease and its complications affect millions of people worldwide. NAFLD (non-alcoholic fatty liver disease) is the liver disease associated with metabolic dysfunction and consists of four stages: steatosis with or without mild inflammation (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. With increased necroinflammation and progression of liver fibrosis, NAFLD may progress to cirrhosis or even hepatocellular carcinoma. Although the underlying mechanisms have not been clearly elucidated in detail, what is clear is that complex immune responses are involved in the pathogenesis of NASH, activation of the innate immune system is critically involved in triggering and amplifying hepatic inflammation and fibrosis in NAFLD/NASH. Additionally, disruption of endoplasmic reticulum (ER) homeostasis in cells, also known as ER stress, triggers the unfolded protein response (UPR) which has been shown to be involved to inflammation and apoptosis. To further develop the prevention and treatment of NAFLD/NASH, it is imperative to clarify the relationship between NAFLD/NASH and innate immune cells and ER stress. As such, this review focuses on innate immune cells and their ER stress in the occurrence of NAFLD and the progression of cirrhosis.

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Section: The Unfolded Protein Responsementioning

confidence: 99%

“…Inhibition of the IRE1α pathway in HSC can reduce both their activation and autophagic activity, resulting in a reduced fibrogenic response ( 34 ). Therefore, XBP1 inhibition may prevent steatohepatitis, and XBP1 is a potential therapeutic target for NASH ( 33 ).…”

Section: The Unfolded Protein Responsementioning

confidence: 99%

Endoplasmic reticulum stress in innate immune cells - a significant contribution to non-alcoholic fatty liver disease

Zhou

Shen²,

Li³

et al. 2022

Front. Immunol.

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“…It is important to mention that activated JNK (P-JNK) level decreases between meals, and fasting overnight alleviates basal low level of P-JNK. Hyper-nutrition type diets activate JNK by metabolites, endoplasmic reticulum (ER) stress, and mitochondrial stress via the modification of acetylation/deacetylation status, transcriptional activation/inhibition, energy metabolism and lipid oxidation, and oxidative stress [ 36 , 37 , 38 ].…”

Section: Hepatic Mapk Family In Metabolic Stress and The Mechanism Of...mentioning

confidence: 99%

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

et al. 2022

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Non-alcoholic fatty liver (NAFL) is the most common chronic liver disease. Activation of mitogen-activated kinases (MAPK) cascade, which leads to c-Jun N-terminal kinase (JNK) activation occurs in the liver in response to the nutritional and metabolic stress. The aberrant activation of MAPKs, especially c-Jun-N-terminal kinases (JNKs), leads to unwanted genetic and epi-genetic modifications in addition to the metabolic stress adaptation in hepatocytes. A mechanism of sustained P-JNK activation was identified in acute and chronic liver diseases, suggesting an important role of aberrant JNK activation in NASH. Therefore, modulation of JNK activation, rather than targeting JNK protein levels, is a plausible therapeutic application for the treatment of chronic liver disease.

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“…In the current issue of Journal of Hepatology, Wang et al take a fresh look at this biology. 3 They study the role of X-box binding protein (XBP)1a mediator of the response to cellular stressin hepatocytes and macrophages in patients and mouse models of liver disease.…”

mentioning

confidence: 99%

“…However, contrary to previous studies, they also show that in these models of liver injury, XBP1 DHep mice are protected in terms of alanine aminotransferase increase and fibrosis. 3 Why hepatocyte-specific deletion of XBP1 is protective against inflammation and fibrosis in some settings but deleterious in others certainly warrants further investigation. Details of the molecular approaches to deleting the gene and the domains needed for lipid metabolism or RIDD activation may be relevant as may the differences in dietary models 12 and duration in the different reports.…”

mentioning

confidence: 99%

Myeloid XBP1 links lipid overload with inflammation in NASH: Do advances in basic science have clinical potential?

Alazawi

2022

Journal of Hepatology

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Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis

Cited by 81 publications

References 44 publications

Endoplasmic reticulum stress in innate immune cells - a significant contribution to non-alcoholic fatty liver disease

Endoplasmic reticulum stress in innate immune cells - a significant contribution to non-alcoholic fatty liver disease

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

Myeloid XBP1 links lipid overload with inflammation in NASH: Do advances in basic science have clinical potential?

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