An Animal Model for the Juvenile Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

Marin, Valérie; Rosso, Natalia; Ben, Matteo Dal; Raseni, Alan; Boschelle, M.; Degrassi, C.; Němečková, Ivana; Nachtigal, Petr; Avellini, Claudio; Tiribelli, Claudio; Gazzin, Silvia

doi:10.1371/journal.pone.0158817

Cited by 50 publications

(69 citation statements)

References 49 publications

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“…Based on previous evidence indicating profound gender-related differences in susceptibilities for liver disease, we have also included separate analyses for men and women. In accordance with recent findings from an animal model for NAFLD [62], our data suggests that alterations in liver enzymes and lipid status among men may occur relatively early in the sequence of events leading abnormal FLI. However, the changes in CRP, a biomarker of inflammation, in response to combined life style risk factors appeared to be more pronounced among women.…”

Section: Discussionsupporting

confidence: 92%

Combined effects of lifestyle risk factors on fatty liver index

et al. 2020

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Background: Factors of lifestyle may have a major impact on liver-related morbidity and mortality. We examined independent and joint effects of lifestyle risk factors on fatty liver index (FLI), a biomarker of hepatic steatosis, in a population-based cross-sectional national health survey. Methods: The study included 12,368 participants (5784 men, 6584 women) aged 25-74 years. Quantitative estimates of alcohol use, smoking, adiposity and physical activity were used to establish a total score of risk factors, with higher scores indicating an unhealthier lifestyle. FLI was calculated based on an algorithm including body mass index, waist circumference, serum gamma-glutamyltransferase and triglycerides. Results: The occurrence of FLI ≥ 60% indicating fatty liver increased from 2.4% in men with zero risk factors to 81.9% in those with a total risk score of 7-8 (p < 0.0005 for linear trend) and in women from 0 to 73.5% (p < 0.0005). The most striking individual impacts on the likelihood for FLI above 60% were observed for physical inactivity (p < 0.0005 for both genders) and alcohol consumption (p < 0.0005 for men). Interestingly, coffee consumption was also found to increase with increasing risk factor scores (p < 0.0005 for linear trend in both genders). Conclusions: The data indicates that unfavorable combinations of lifestyle risk factors lead to a high likelihood of hepatic steatosis. Use of FLI as a diagnostic tool may benefit the assessment of interventions aimed at maintaining a healthy lifestyle and prevention of liver-related morbidity.

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Section: Discussionsupporting

confidence: 92%

Combined effects of lifestyle risk factors on fatty liver index

et al. 2020

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“…To determine whether DUSP12 deficiency could promote liver inflammation and fibrosis in NASH, we established a NASH model using an HFHC diet in mice . Like the HFD‐induced response, body weight was similar, while liver weight was significantly increased in DUSP12‐CKO mice compared with control mice (Fig.…”

Section: Resultsmentioning

confidence: 98%

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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“…This situation is even more serious if the paediatric population is considered, with the prevalence of obesity increasing from 0.7% in 1975 to 5.6% in 2016 in girls, and from 0.9% to 7.8% in boys . Because the progression from FL to NASH is more rapid and aggressive in children than in adults, this is especially worrisome because obesity in early life increases the risk of both cirrhosis and HCC in adulthood.…”

Section: The Dimension Of the Problem Worldwidementioning

confidence: 99%

Global epidemiology of non‐alcoholic fatty liver disease/non‐alcoholic steatohepatitis: What we need in the future

Araújo

Rosso

Bedogni

et al. 2018

Liver International

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The estimated prevalence of non‐alcoholic fatty liver disease (NAFLD) worldwide is approximately 25%. However, the real prevalence of NAFLD and the associated disorders is unknown mainly because reliable and applicable diagnostic tests are lacking. This is further complicated by the lack of consensus on the terminology of different entities such as NAFLD or nonalcoholic steatohepatitis (NASH). Although assessing fatty infiltration in the liver is simple by ultrasound, the gold standard for the assessment of fibrosis, the only marker of progression towards more severe liver disease is still liver biopsy. Although other non‐invasive tests have been proposed, they must still be validated in large series. Because NAFL/NAFLD/NASH and related metabolic diseases represent an economic burden, finding an inexpensive method to diagnose and stage fatty liver is a priority. A translational approach with the use of cell and/or animal models could help to reach this goal.

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An Animal Model for the Juvenile Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

Cited by 50 publications

References 49 publications

Combined effects of lifestyle risk factors on fatty liver index

Combined effects of lifestyle risk factors on fatty liver index

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

Global epidemiology of non‐alcoholic fatty liver disease/non‐alcoholic steatohepatitis: What we need in the future

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