Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet‐induced obese and biopsy‐confirmed mouse model of NASH

Møllerhøj, Mathias Bonde; Veidal, Sanne Skovgård; Thrane, Kirstine Tølbøl; Oró, Denise; Overgaard, Agnete; Salinas, Casper Gravesen; Madsen, Martin Rønn; Pfisterer, Larissa; Vyberg, Mogens; Simon, Eric J.; Broermann, Andre; Vrang, Niels; Jelsing, Jacob; Feigh, Michael; Hansen, Henrik H.

doi:10.1111/cts.13235

Cited by 33 publications

(32 citation statements)

References 65 publications

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“…In contrast, most previous models did not examine these factors important for human HCC (Table 1). While similar to our findings, a recent study also found consistent NASH and HCC development with HF/Chol/SD in C57BL/6J mice, 49 whereas p62 accumulation and association with poor prognosis of HCC in humans were not examined. Furthermore, the 2% high cholesterol diet used has been considered to cause “toxic steatohepatitis” and is less physiologically relevant 51 .…”

Section: Discussionsupporting

confidence: 91%

“…Methionine‐ and choline‐deficient diets promote steatosis and fibrosis; however, this model causes rapid weight loss, does not result in HCC, and does not mimic the etiology and metabolic features of human NASH 47 . Accumulating evidence has shown that progression toward hepatocellular ballooning, a hallmark of NASH, and fibrosis with HFD requires additional dietary manipulations, such as a choline‐deficient diet or HFD combined with high cholesterol and sugar diet (HF/Chol/SD) 48,49 . Nevertheless, while choline‐deficient HFD causes a NASH phenotype as well as HCC, the penetrance of HCC induction is very low 48 .…”

Section: Discussionmentioning

confidence: 99%

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A new preclinical model of western diet‐induced progression of non‐alcoholic steatohepatitis to hepatocellular carcinoma

et al. 2022

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Non‐alcoholic steatohepatitis (NASH) results from the accumulation of excessive liver lipids leading to hepatocellular injury, inflammation, and fibrosis that greatly increase the risk for hepatocellular carcinoma (HCC). Despite the well‐characterized clinical and histological pathology for NASH‐driven HCC in humans, its etiology remains unclear and there is a deficiency in pre‐clinical models that recapitulate the progression of the human disease. Therefore, we developed a new mouse model amenable to genetic manipulations and gene targeting that mimics the gradual NASH to HCC progression observed in humans. C57BL/6NJ mice were fed a Western high‐fat diet and sugar water (HFD/SW) and monitored for effects on metabolism, liver histology, tumor development, and liver transcriptome for up to 54 weeks. Chronic HFD/SW feeding led to significantly increased weight gain, serum and liver lipid levels, liver injury, and glucose intolerance. Hepatic pathology progressed and mice developed hepatocellular ballooning, inflammation, and worse fibrosis was apparent at 16 weeks, greatly increased through 32 weeks, and remained elevated at 54 weeks. Importantly, hepatocellular cancer spontaneously developed in 75% of mice on HFD/SW, half of which were HCC, whereas none of the mice on the chow diet developed HCC. Chronic HFD/SW induced molecular markers of de novo lipogenesis, endoplasmic reticulum stress, inflammation, and accumulation of p62, all of which also participate in the human pathology. Moreover, transcriptome analysis revealed activation of HCC‐related genes and signatures associated with poor prognosis of human HCC. Overall, we have identified a new preclinical model that recapitulates known hallmarks of NASH‐driven HCC that can be utilized for future molecular mechanistic studies of this disease.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

A new preclinical model of western diet‐induced progression of non‐alcoholic steatohepatitis to hepatocellular carcinoma

et al. 2022

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“…17 Recent clinical and experimental studies have shown that Semaglutide can dramatically improve liver function and lipid accumulation in NAFLD or NASH. [20][21][22] However, so far, the regulatory mechanism of Semaglutide for NAFLD remains to be further studied. Our study evaluated the therapeutic effect of Semaglutide on hepatic fat accumulation in NAFLD combined with T2DM mice.…”

Section: Discussionmentioning

confidence: 99%

“… 21 In addition, Semaglutide robustly reduced hepatomegaly and liver biochemical markers in Gubra-Amylin NASH (GAN) diet-induced obese (DIO) -NASH mice after 8 weeks of Semaglutide treatment. 22 Although the above-mentioned studies have suggested that Semaglutide has ameliorating effects on NAFLD, the underlying mechanisms of these benefits have not been confirmed.…”

Section: Introductionmentioning

confidence: 99%

Semaglutide May Alleviate Hepatic Steatosis in T2DM Combined with NFALD Mice via miR-5120/ABHD6

Li¹,

Ye²,

She³

et al. 2022

DDDT

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Objective Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) has been extensively studied, the role of its underlying pathogenesis remains unclear, and there is currently no approved therapeutic strategy for NAFLD. The purpose of this study was to observe the beneficial effects of Semaglutide on NAFLD in vivo and in vitro, as well as its potential molecular mechanisms. Methods Semaglutide was used to treat type 2 diabetes mellitus (T2DM) combined with NAFLD mice for 12 weeks. Hepatic function and structure were evaluated by liver function, blood lipids, liver lipids, H&E staining, oil red staining and Sirius staining. The expression of α/β hydrolase domain-6 (ABHD6) was measured by qPCR and Western blotting in vivo and in vitro. Then, dual-luciferase reporter assay was performed to verify the regulation of the upstream miR-5120 on ABHD6. Results Our data revealed that Semaglutide administration significantly improved liver function and hepatic steatosis in T2DM combined with NAFLD mice. Furthermore, compared with controls, up-regulation of ABHD6 and down-regulation of miR-5120 were found in the liver of T2DM+NAFLD mice and HG+FFA-stimulated Hepa 1–6 hepatocytes. Interestingly, after Semaglutide intervention, ABHD6 expression was significantly decreased in the liver of T2DM+NAFLD mice and in HG+FFA-stimulated Hepa 1–6 hepatocytes, while miR-5120 expression was increased. We also found that miR-5120 could regulate the expression of ABHD6 in hepatocytes, while Semaglutide could modulate the expression of ABHD6 through miR-5120. In addition, GLP-1R was widely expressed in mouse liver tissues and Hepa 1–6 cells. Semaglutide could regulate miR-5120/ABHD6 expression through GLP-1R. Conclusion Our data revealed the underlying mechanism by which Semaglutide improves hepatic steatosis in T2DM+NAFLD, and might shed new light on the pathological role of miR-5120/ABHD6 in the pathogenesis of T2DM+NAFLD.

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“…In a diet composition matched study, the use of a nontrans-fat GAN model was comparable in systemic metabolic dysregulation effects and liver disease progression to that of the AMLN diet (or trans-fat version) [ 184 , 187 ]. Hence, both AMLN [ 188 ] and GAN diets [ 189 , 190 , 191 ] are still used in many clinical-translation interventional studies today. In fact, evidence suggests that the type of fatty acid used in the diet contributes to differential effects in MAFLD [ 185 , 192 ].…”

Section: Mafld Preclinical Modelsmentioning

confidence: 99%

Utility of Human Relevant Preclinical Animal Models in Navigating NAFLD to MAFLD Paradigm

Chua

Low

Cheam

et al. 2022

IJMS

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Fatty liver disease is an emerging contributor to disease burden worldwide. The past decades of work established the heterogeneous nature of non-alcoholic fatty liver disease (NAFLD) etiology and systemic contributions to the pathogenesis of the disease. This called for the proposal of a redefinition in 2020 to that of metabolic dysfunction-associated fatty liver disease (MAFLD) to better reflect the current understanding of the disease. To date, several clinical cohort studies comparing NAFLD and MAFLD hint at the relevancy of the new nomenclature in enriching for patients with more severe hepatic injury and extrahepatic comorbidities. However, the underlying systemic pathogenesis is still not fully understood. Preclinical animal models have been imperative in elucidating key biological mechanisms in various contexts, including intrahepatic disease progression, interorgan crosstalk and systemic dysregulation. Furthermore, they are integral in developing novel therapeutics against MAFLD. However, substantial contextual variabilities exist across different models due to the lack of standardization in several aspects. As such, it is crucial to understand the strengths and weaknesses of existing models to better align them to the human condition. In this review, we consolidate the implications arising from the change in nomenclature and summarize MAFLD pathogenesis. Subsequently, we provide an updated evaluation of existing MAFLD preclinical models in alignment with the new definitions and perspectives to improve their translational relevance.

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Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet‐induced obese and biopsy‐confirmed mouse model of NASH

Cited by 33 publications

References 65 publications

A new preclinical model of western diet‐induced progression of non‐alcoholic steatohepatitis to hepatocellular carcinoma

A new preclinical model of western diet‐induced progression of non‐alcoholic steatohepatitis to hepatocellular carcinoma

Semaglutide May Alleviate Hepatic Steatosis in T2DM Combined with NFALD Mice via miR-5120/ABHD6

Utility of Human Relevant Preclinical Animal Models in Navigating NAFLD to MAFLD Paradigm

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