The role of IFN in the development of NAFLD and NASH

Møhlenberg, Michelle; Terczyńska-Dyla, Ewa; Thomsen, Karen Louise; George, Jacob; Eslam, Mohammed; Grønbæk, Henning; Hartmann, Rune

doi:10.1016/j.cyto.2018.08.013

Cited by 34 publications

(28 citation statements)

References 84 publications

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“…While NAFLD is mostly benign, chronic liver inflammation in NASH may cause progression to fibrosis and hepatocellular carcinoma. Currently, the need for a better understanding of the reasons that drive the progression from NAFLD to NASH and how to use this information both to improve diagnosis and to develop treatment strategies is extremely urgent . Intriguingly, our findings identify a function of DUSP12 in regulating lipid metabolism.…”

Section: Discussionmentioning

confidence: 84%

Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal–Regulating Kinase 1 Pathways

Huang

Zhang

et al. 2019

Hepatology

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Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Due to the growing economic burden of NAFLD on public health, it has become an emergent target for clinical intervention. DUSP12 is a member of the dual specificity phosphatase (DUSP) family, which plays important roles in brown adipocyte differentiation, microbial infection, and cardiac hypertrophy. However, the role of DUSP12 in NAFLD has yet to be clarified. Here, we reveal that DUSP12 protects against hepatic steatosis and inflammation in L02 cells after palmitic acid/oleic acid treatment. We demonstrate that hepatocyte specific DUSP12-deficient mice exhibit high-fat diet (HFD)-induced and high-fat high-cholesterol diet-induced hyperinsulinemia and liver steatosis and decreased insulin sensitivity. Consistently, DUSP12 overexpression in hepatocyte could reduce HFDinduced hepatic steatosis, insulin resistance, and inflammation. At the molecular level, steatosis in the absence of DUSP12 was characterized by elevated apoptosis signal-regulating kinase 1 (ASK1), which mediates the mitogenactivated protein kinase (MAPK) pathway and hepatic metabolism. DUSP12 physically binds to ASK1, promotes its dephosphorylation, and inhibits its action on ASK1-related proteins, JUN N-terminal kinase, and p38 MAPK in order to inhibit lipogenesis under high-fat conditions. Conclusion: DUSP12 acts as a positive regulator in hepatic steatosis and offers potential therapeutic opportunities for NAFLD. (Hepatology 2019;70:1099-1118). SEE EDITORIAL ON PAGE 1091N onalcoholic fatty liver disease (NAFLD) is the most common diffuse liver disease and is characterized by lipid accumulation in hepatocytes in the absence of excessive alcohol consumption. (1) The prevalence of NAFLD increases worryingly with obesity and other diseases of metabolic syndrome (MS) and is expected to be the leading cause of liver failure in the future. (2) Accumulating studies show that NAFLD not only is linked to an increased risk of liver-related mortality or morbidity

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Section: Discussionmentioning

confidence: 84%

Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal–Regulating Kinase 1 Pathways

Huang

Zhang

et al. 2019

Hepatology

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“…Based on genetic data, unique properties have been attributed to the IFNL4 gene. IFNL4 protects against liver fibrosis (17,19), and hence it is assumed to help dampen or control inflammation in both HCV-infected patients and patients with nonalcoholic steatosis (NASH) (15). Furthermore, its ablation facilitates both spontaneous and treatment-induced HCV clearance (12).…”

Section: Discussionmentioning

confidence: 99%

“…Surprisingly, patients harboring the functional IFNL4-ΔG allele have a lower HCV clearance rate than that of patients who have the IFNL4-TT allele (12). Interestingly, the IFNL4-ΔG allele is also associated with lower levels of liver inflammation and fibrosis in HCV-infected patients (15)(16)(17), as well as in patients with nonalcoholic fatty liver disease (18,19). Thus, the genetic evidence suggests that in vivo, the IFNL4 gene acts in a proviral and anti-inflammatory manner, quite in contrast to the proinflammatory and antiviral effect of other type III IFNs.…”

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confidence: 99%

The IFNL4 Gene Is a Noncanonical Interferon Gene with a Unique but Evolutionarily Conserved Regulation

Zhou

Møhlenberg

Terczyńska-Dyla

et al. 2020

J Virol

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Interferon lambda 4 (IFN-λ4) is a recently identified enigmatic member of the interferon (IFN) lambda family. Genetic data suggest that the IFNL4 gene acts in a proviral and anti-inflammatory manner in patients. However, the protein is indistinguishable in vitro from the other members of the interferon lambda family. We have investigated the gene regulation of IFNL4 in detail and found that it differs radically from that of canonical antiviral interferons. Being induced by viral infection is a defining characteristic of interferons, but viral infection or overexpression of members of the interferon regulatory factor (IRF) family of transcription factors only leads to a minute induction of IFNL4. This behavior is evolutionarily conserved and can be reversed by inserting a functional IRF3 binding site into the IFNL4 promoter. Thus, the regulation of the IFNL4 gene is radically different and might explain some of the atypical phenotypes associated with the IFNL4 gene in humans. IMPORTANCE Recent genetic evidence has highlighted how the IFNL4 gene acts in a counterintuitive manner, as patients with a nonfunctional IFNL4 gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation. This suggests that the IFNL4 gene acts in a proviral and anti-inflammatory manner. These surprising but quite clear genetic data have prompted an extensive examination of the basic characteristics of the IFNL4 gene and its gene product, interferon lambda 4 (IFN-λ4). We have investigated the expression of the IFNL4 gene and found it to be poorly induced by viral infections. A thorough investigation of the IFNL4 promoter revealed a highly conserved and functional promoter, but also one that lacks the defining characteristic of interferons (IFNs), i.e., the ability to be effectively induced by viral infections. We suggest that the unique function of the IFNL4 gene is related to its noncanonical transcriptional regulation.

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“…At least five common variants in different genes have been associated with NAFLD, namely PNPLA3, transmembrane 6 superfamily member 2 (TM6SF2), glucokinase regulator (GCKR), MBOAT7, and hydroxysteroid 17-beta dehydrogenase-13 (HSD17B13) 140 . Multiple other genes have reported associations, including polymorphisms in inflammatory, immune and metabolism-related, oxidative stress, adipokine, and myokinerelated genes [139][140][141][142][143][144] . It is noteworthy however that all known variants explain only a small proportion of NAFLD, suggesting the existence of heritability factors that are yet to be defined 145 .…”

Section: Genetic Variationmentioning

confidence: 99%

MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease

2020

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Competing interest's statement: Rajiv Jalan has research collaborations with Takeda, and Yaqrit, and consults for Akaza and Yaqrit. Rajiv Jalan is the founder of Yaqrit Limited, which is developing UCL inventions for treatment of patients with cirrhosis. Rajiv Jalan is an inventor of ornithine phenylacetate, which was licensed by UCL to Mallinckrodt. He is also the inventor of Yaq-001, DIALIVE and Yaq-005, the patents for which have been licensed by his University into a UCL spinout company, Yaqrit Ltd. The rest of authors declare no competing interests for this manuscript.

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The role of IFN in the development of NAFLD and NASH

Cited by 34 publications

References 84 publications

Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal–Regulating Kinase 1 Pathways

Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal–Regulating Kinase 1 Pathways

The IFNL4 Gene Is a Noncanonical Interferon Gene with a Unique but Evolutionarily Conserved Regulation

MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease

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