A Novel Mouse Model of Nonalcoholic Steatohepatitis Suggests that Liver Fibrosis Initiates around Lipid-Laden Macrophages

Ichimura‐Shimizu, Mayuko; Tsuchiyama, Yosuke; Morimoto, Yuki; Matsumoto, Minoru; Kobayashi, Tomoko; Sumida, Satoshi; Kakimoto, Takumi; Oya, Takeshi; Ogawa, Hirohisa; Yamashita, Michiko; Matsuda, Satoru; Omagari, Katsuhisa; Taira, Shu; Tsuneyama, Koichi

doi:10.1016/j.ajpath.2021.10.002

Cited by 7 publications

(6 citation statements)

References 43 publications

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Section: Discussionmentioning

confidence: 99%

“…Neutrophils are a leukocyte population that, with macrophages [24][25][26][27][28][29][30][31][32][33][34][35], are the earliest to accumulate in insulin-sensitive tissues with weight gain [12,50,51]. We therefore tested whether targeting only neutrophil accumulation independently of macrophages-whose role is already well-established in the progression of NAFLD/ NASH [24][25][26][27][28][29][30][31][32][33][34][35]-could improve insulin sensitivity, prevent the progression of HFD-induced IR, and possibly prevent the progression towards a liver pathology that could be prodromal of, and/or precipitate NAFLD/ NASH. Despite a mechanistic rationale linking neutrophils and CXCR2 to IR and possibly IR-associated NAFLD [17], to date, there are no studies aimed at shortcircuiting only neutrophil function and only neutrophil-driven inflammation in progressive obesity-driven metabolic dysregulation that results in IR and associated liver pathology precipitating NAFLD/NASH.…”

Section: Discussionmentioning

confidence: 99%

“…This single agent, or other agents in its class, may prove useful as adjunctives to T2D/metabolic syndrome standard of care. As our cellular targets of interest were neutrophils, we did not examine the effect of AZD5069 on macrophages, an important cell population involved in the effects of HFD on the progression towards liver pathology [24][25][26][27][28][29][30][31][32][33][34][35]. We expect that arresting neutrophil migration and activity will impact macrophage accumulation and function and thus, in an indirect manner, AZD5069 is expected to affect macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…CXCR2 ligands are expressed in the pancreas, adipose and liver [22], suggesting that under potentiallystressful states, their secretion can be expected to recruit and activate neutrophils, which in turn would exacerbate and amplify a low grade inflammatory condition [23]. In spite of the evidence linking neutrophils and CXCR2 to T2D and possibly T2D-associated NAFLD [17], to date there are no studies aimed at short-circuiting neutrophil function and neutrophil-driven inflammation independently of macrophages-well known participants in the progression of HFD pathology towards NAFLD/NASH [24][25][26][27][28][29][30][31][32][33][34][35]-in progressive obesity-driven metabolic dysregulation that results in T2D and associated NAFLD. Herein, we show for the first time, using the selective CXCR2 antagonist AZD5069 in high fat fed mice, improved insulin-induced suppression of hepatic glucose production, decreased hepatic lipid storage, and a significant prevention of progression towards liver pathology reminiscent of NAFLD.…”

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confidence: 99%

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Improvement in insulin sensitivity and prevention of high fat diet-induced liver pathology using a CXCR2 antagonist

Phillips

Lantier

Engman

et al. 2022

Cardiovasc Diabetol

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Background Liver pathology (LP) characteristic of non-alcoholic fatty acid disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is a prevalent co-morbidity of type 2 diabetes (T2D). Accumulating evidence indicates that neutrophils driving insulin resistance (IR), including hepatic IR, precipitate T2D-associated NAFLD/NASH. We hypothesized that targeting neutrophil accumulation into insulin-sensitive tissues in mice using a CXCR2 antagonist under T2D-precipitating high fat diet (HFD) could improve insulin sensitivity and prevent the progression towards liver pathology reminiscent of NAFLD/NASH. Methods Mice were age-matched and on standard rodent chow prior to 1:1 randomization into control and HFD formulated with the CXCR2 antagonist AZD5069 or with biologically inactive substitute. They were monitored for metabolic changes including insulin sensitivity using the hyperinsulinemic-euglycemic clamp and hepatic histopathologic evaluation in H&E-stained sections as well as via immunofluorescence microscopy of liver sections for leukocyte markers, collagen 1A1 formation, α-smooth muscle actin (SMA), and galectin-3 expression, for 16 weeks. Statistical tests used to determine significant differences among study groups and outcomes include Student’s t-test, one-way ANOVA, repeated measures two-way ANOVA, and Fisher’s exact test, depending on the analytical question. Results Compared to mice on HFD, mice in the AZD5069-formulated HFD exhibited improved insulin sensitivity, a modest reduction in weight gain, and a significant improvement in LP and markers related to NAFLD/NASH. Mice in the AZD5069-formulated HFD also exhibited reduced neutrophil accumulation into the liver at the end of the 16 week study period. Conclusions These results show, for the first time, the effectiveness of a selective CXCR2 antagonist to improve insulin sensitivity, concomitantly preventing the progression towards LP characteristic of NAFLD/NASH. This represents a novel approach to target IR and developing LP under T2D-susceptible conditions using a single agent. Furthermore, our data extend the growing evidence in support of neutrophils as a leukocyte population that imprints and maintains a chronic inflammatory state in the progression of dysregulated metabolism in liver-specific co-morbid conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Improvement in insulin sensitivity and prevention of high fat diet-induced liver pathology using a CXCR2 antagonist

Phillips

Lantier

Engman

et al. 2022

Cardiovasc Diabetol

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show abstract

“…In NASH patients and mice, macrophages typically accumulate in clusters around the steatotic hepatocytes and can promote the progression of NAFL to NASH ( 44 , 45 ). In addition, a high-fat/cholesterol/cholic acid diet mouse model that assembles NASH-associated fibrosis also showed that liver fibrosis is initiated around lipid-associated macrophages ( 46 ). More interestingly, Anneleen et al.…”

Section: Msr1 Accelerates Nafld Progressionmentioning

confidence: 99%

Role of macrophage scavenger receptor MSR1 in the progression of non-alcoholic steatohepatitis

Sheng

Zhang

2022

Front. Immunol.

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Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD), and the dysregulation of lipid metabolism and oxidative stress are the typical features. Subsequent dyslipidemia and oxygen radical production may render the formation of modified lipids. Macrophage scavenger receptor 1 (MSR1) is responsible for the uptake of modified lipoprotein and is one of the key molecules in atherosclerosis. However, the unrestricted uptake of modified lipoproteins by MSR1 and the formation of cholesterol-rich foamy macrophages also can be observed in NASH patients and mouse models. In this review, we highlight the dysregulation of lipid metabolism and oxidative stress in NASH, the alteration of MSR1 expression in physiological and pathological conditions, the formation of modified lipoproteins, and the role of MSR1 on macrophage foaming and NASH development and progression.

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PPARs: modulating lipotoxicity and thus inhibiting fibrosis

Li,

Zhang,

Wang

2024

Hormones

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A Novel Mouse Model of Nonalcoholic Steatohepatitis Suggests that Liver Fibrosis Initiates around Lipid-Laden Macrophages

Cited by 7 publications

References 43 publications

Improvement in insulin sensitivity and prevention of high fat diet-induced liver pathology using a CXCR2 antagonist

Improvement in insulin sensitivity and prevention of high fat diet-induced liver pathology using a CXCR2 antagonist

Role of macrophage scavenger receptor MSR1 in the progression of non-alcoholic steatohepatitis

PPARs: modulating lipotoxicity and thus inhibiting fibrosis

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