Mouse models of nonalcoholic steatohepatitis in preclinical drug development

Hansen, Henrik H.; Feigh, Michael; Veidal, Sanne Skovgård; Rigbolt, Kristoffer T.G.; Vrang, Niels; Fosgerau, Keld

doi:10.1016/j.drudis.2017.06.007

Cited by 196 publications

(199 citation statements)

References 119 publications

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“…Our opinion is that any significant progress in these fronts depends on the availability of mouse models that closely mimic human NASH. Since mouse models of NASH have been recently reviewed (Haczeyni et al, 2018; Hansen et al, 2017; Takakura et al, 2018), we focus the following discussion on preclinical models for studying NASH-driven HCC, the most dangerous outcome of untreated NASH. In addition to replicating the human pathology and showing robust progression to HCC within a reasonable timeframe (less than 12 months) and without the use of chemical carcinogens, a suitable preclinical model of NASH-driven HCC should also be responsive to the only effective HCC treatment identified thus far, inhibitors of the PD-L1:PD-1 checkpoint (El-Khoueiry et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?

et al. 2019

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Hepatocellular carcinoma (HCC) is one of the most fatal and fastest growing cancers. Recently, nonalcoholic steatohepatitis (NASH) has been recognized as a major HCC catalyst. However, it is difficult to decipher the molecular mechanisms underlying the pathogenesis of NASH and understand how it progresses to HCC by studying humans. Progress in this field depends on the availability of reliable preclinical models amenable to genetic and functional analyses and exhibit robust NASH to HCC progression. Although numerous mouse models of NASH have been described, many do not faithfully mimic the human disease and few reliably progress to HCC. Here, we review current literature on the molecular etiology of NASH-related HCC and critically evaluate existing mouse models and their suitability for studying this malignancy. We also compare human transcriptomic and histopathological profiles with data from MUP-uPA mice, a reliable model of NASH-driven HCC that has been useful for evaluation of HCC-targeting immunotherapies.

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Section: Introductionmentioning

confidence: 99%

Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?

et al. 2019

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“…NASH is now the leading cause of liver transplantation in the United States and predisposes to HCC (2), the most common malignancy of liver worldwide (3). Currently, there are no FDA-approved treatments for NASH, which could be a reflection of the lack of faithful animal models that fully recapitulate its clinical presentation (4,5).…”

Section: Introductionmentioning

confidence: 99%

“…NASH pathogenesis is complex and multi-factorial, though the risk factors are nearly identical to those predisposing to the metabolic syndrome (4). It was revealed nearly two decades ago that NAFLD is significantly associated with insulin resistance (IR) (6), and NAFLD-associated hepatic IR is independent of adiposity and glucose intolerance (7).…”

Section: Introductionmentioning

confidence: 99%

Adipocyte JAK2 mediates aging-associated metabolic liver disease and progression to hepatocellular carcinoma

Corbit

Wilson

Lowe

et al. 2019

Preprint

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Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are liver manifestations of the metabolic syndrome and can progress to hepatocellular carcinoma (HCC). Loss of Growth Hormone (GH) signaling is reported to predispose to NAFLD and NASH through direct actions on the liver. Here, we report that aged mice lacking hepatocyte Jak2 (JAK2L), an obligate transducer of Growth Hormone (GH) signaling, spontaneously develop the full spectrum of phenotypes found in patients with metabolic liver disease, beginning with insulin resistance and lipodystrophy and manifesting as NAFLD, NASH and even HCC, independent of dietary intervention. Remarkably, insulin resistance, metabolic liver disease, and carcinogenesis are prevented in JAK2L mice via concomitant deletion of adipocyte Jak2 (JAK2LA). Further, we demonstrate that GH increases hepatic lipid burden but does so indirectly via signaling through adipocyte JAK2. Collectively, these data establish adipocytes as the mediator of GH-induced metabolic liver disease and carcinogenesis. In addition, we report a new spontaneous model of NAFLD, NASH, and HCC that recapitulates the natural sequelae of human insulin resistance-associated disease progression. The work presented here suggests a attention be paid towards inhibition of adipocyte GH signaling as a therapeutic target of metabolic liver disease.

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“…Animal models of NASH can be roughly categorized into those caused by genetic mutation and those with an acquired phenotype induced via dietary manipulation. Genetic leptin‐deficient (ob/ob), leptin‐resistant (db/db), or Agouti mutation (KK/A y ) mice, and methionine/choline‐deficient (MCD) diet, CDAA diet‐, or high‐fat diet‐fed models (Anstee & Goldin, ; Ibrahim, Hirsova, Malhi, & Gores, ; Nakamura & Terauchi, ) are examples of animal models of NASH that have been used to examine a number of traditional and novel agents to date (Hansen et al, ). We previously examined the effects of ipragliflozin on NAFLD and NASH using CDAA diet‐fed rats, KK/A y , high‐fat diet‐fed streptozotocin–nicotinamide‐induced type 2 diabetic mice (Hayashizaki‐Someya et al, ; Tahara et al, ; Tahara, Takasu, Yokono, Imamura, & Kurosaki, ).…”

Section: Discussionmentioning

confidence: 99%

SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone prevents progression of nonalcoholic steatohepatitis in a type 2 diabetes rodent model

Tahara

Takasu

2019

Physiol Rep

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Nonalcoholic steatohepatitis (NASH) has become the most common cause of chronic liver disease worldwide in recent years. The pathogenesis of NASH is closely linked to metabolic diseases such as insulin resistance, obesity, dyslipidemia, and type 2 diabetes. However, there is currently no pharmacological agent for preventing the progression of NASH. Sodium–glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion by inhibiting renal glucose reabsorption, and improve various pathological conditions of type 2 diabetes, including insulin resistance. In the present study, we examined the effects of ipragliflozin, a SGLT2‐selective inhibitor, alone and in combination with pioglitazone on NASH in high‐fat diet‐fed KK/Ay type 2 diabetic mice. Type 2 diabetic mice with NASH exhibited steatosis, inflammation, and fibrosis in the liver as well as hyperglycemia, insulin resistance, and obesity, features that are observed in human NASH. Four‐week repeated administration of ipragliflozin (0.1–3 mg/kg) led to significant improvements in hyperglycemia, insulin resistance, and obesity in addition to hyperlipidemia and liver injury including hepatic steatosis and fibrosis. Moreover, ipragliflozin reduced inflammation and oxidative stress in the liver. Repeated administration of pioglitazone (3–30 mg/kg) also significantly improved various parameters of diabetes and NASH, excluding obesity. Furthermore, combined treatment comprising ipragliflozin (1 mg/kg) and pioglitazone (10 mg/kg) additively improved these parameters. These findings indicate that the SGLT2‐selective inhibitor ipragliflozin improves hyperglycemia as well as NASH in type 2 diabetic mice. Therefore, treatment with ipragliflozin monotherapy or coadministered with pioglitazone is expected to be a potential therapeutic option for the treatment of type 2 diabetes with NASH.

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Mouse models of nonalcoholic steatohepatitis in preclinical drug development

Cited by 196 publications

References 119 publications

Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?

Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?

Adipocyte JAK2 mediates aging-associated metabolic liver disease and progression to hepatocellular carcinoma

SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone prevents progression of nonalcoholic steatohepatitis in a type 2 diabetes rodent model

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