Dataset Information

Characterization of the CDAA Diet-Induced Non-alcoholic Steatohepatitis Model: Sex-Specific Differences in Inflammation, Fibrosis, and Cholesterol Metabolism in Middle-Aged Mice.

ABSTRACT:

Background

The prevalence of non-alcoholic steatohepatitis (NASH) rapidly increases with associated metabolic disorders such as dyslipidemia; therefore, NASH is now considered an independent risk factor of cardiovascular diseases. NASH displays sex-linked epidemiological, phenotypical, and molecular differences; however, little is known about the background of these sex-specific differences on the molecular level.

Objectives

We aimed to assess sex-specific differences in the expression of inflammatory and fibrotic genes, as well as in cholesterol metabolism, focusing on the expression of Pcsk9 in several tissues in a mouse model of NASH that shows the typical features of the human condition.

Methods and results

We fed 10-months-old male and female C57Bl/6J mice with a NASH-inducing CDAA or corresponding control diet for 8 weeks. We found that, compared to the control male mice baseline, hepatic Pcsk9 expression as well as serum PCSK9 level was significantly higher in females, and both circulating PCSK9 level and the hepatic Pcsk9 gene were markedly decreased in female mice during NASH development. Histological analysis revealed that male and female mice develop a similar degree of steatosis; however, fibrosis was more pronounced in males upon CDAA diet feeding. Strikingly, female mice have higher hepatic expression of the pro-inflammatory cytokines (Il1b, Ifng), and increased IL-1? cleavage by the NLRP3 inflammasome, and a decrease in Clec4f⁺ resident Kupffer cell population in comparison to males in the CDAA-fed groups.

Conclusion

This is the first demonstration that there are critical sex-specific differences during NASH development in middle-aged mice regarding inflammation, fibrosis, and cholesterol metabolism and that changes in PCSK9 and IL-1? are likely important contributors to sex-specific changes during the transition to NASH.

SUBMITTER: Kucsera D

PROVIDER: S-EPMC7937716 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Characterization of the CDAA Diet-Induced Non-alcoholic Steatohepatitis Model: Sex-Specific Differences in Inflammation, Fibrosis, and Cholesterol Metabolism in Middle-Aged Mice.

Kucsera Dániel D Tóth Viktória E VE Gergő Dorottya D Vörös Imre I Onódi Zsófia Z Görbe Anikó A Ferdinandy Péter P Varga Zoltán V ZV

Frontiers in physiology 20210222

<h4>Background</h4>The prevalence of non-alcoholic steatohepatitis (NASH) rapidly increases with associated metabolic disorders such as dyslipidemia; therefore, NASH is now considered an independent risk factor of cardiovascular diseases. NASH displays sex-linked epidemiological, phenotypical, and molecular differences; however, little is known about the background of these sex-specific differences on the molecular level.<h4>Objectives</h4>We aimed to assess sex-specific differences in the expre ...[more]

PMID: 33692700

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Project description:The fatty acid translocase, also known as CD36, is a well-established scavenger receptor for fatty acid (FA) uptake and is abundantly expressed in many metabolically active tissues. In the liver, CD36 is known to contribute to the progression of non-alcoholic fatty liver disease and to the more severe non-alcoholic steatohepatitis, by promoting triglyceride accumulation and subsequent lipid-induced endoplasmic reticulum (ER) stress. Given the recent discovery that the hepatocyte-secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) blocks CD36 expression, we sought to investigate the role of PCSK9 in liver fat accumulation and injury in response to saturated FAs and in a mouse model of diet-induced hepatic steatosis. Methods:In this study, we investigated the role of PCSK9 on the uptake and accumulation of FAs, as well as FA-induced toxicity, in a variety of cultured hepatocytes. Diet-induced hepatic steatosis and liver injury were also assessed in Pcsk9 -/- mice. Results:Our results indicate that PCSK9 deficiency in cultured hepatocytes increased the uptake and accumulation of saturated and unsaturated FAs. In the presence of saturated FAs, PCSK9 also protected cultured hepatocytes from ER stress and cytotoxicity. In line with these findings, a metabolic challenge using a high-fat diet caused severe hepatic steatosis, ER stress inflammation and fibrosis in the livers of Pcsk9 -/- mice compared to controls. Given that inhibition of CD36 ablated the observed accumulation of lipid in vitro and in vivo, our findings also highlight CD36 as a strong contributor to steatosis and liver injury in the context of PCSK9 deficiency. Conclusions:Collectively, our findings demonstrate that PCSK9 regulates hepatic triglyceride content in a manner dependent on CD36. In the presence of excess dietary fats, PCSK9 can also protect against hepatic steatosis and liver injury. Lay summary:The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein known to reduce the abundance of receptors on the surface of liver cells charged with the task of lipid uptake from the circulation. Although PCSK9 deficiency is known to cause lipid accumulation in mice and in cultured cells, the toxicological implications of this observation have not yet been reported. In this study, we demonstrate that PCSK9 can protect against cytotoxicity in cultured liver cells treated with a saturated fatty acid and we also show that Pcsk9 knockout mice develop increased liver injury in response to a high-fat diet.

Project description:Non-alcoholic steatohepatitis (NASH) is the leading cause of chronic liver injury and the third most common reason for liver transplantations in Western countries. It is unclear so far how different fat sources in Western diets (WD) influence the development of NASH. Our study investigates the impact of non-trans fat (NTF) and corn oil (Corn) as fat source in a WD mouse model of steatohepatitis on disease development and progression. C57BL/6J wildtype (WT) mice were fed "standard" WD (WD-Std), WD-NTF or WD-Corn for 24 weeks. WT animals treated with WD-NTF exhibit distinct features of the metabolic syndrome compared to WD-Std and WD-Corn. This becomes evident by a worsened insulin resistance and elevated serum ALT, cholesterol and triglyceride (TG) levels compared to WD-Corn. Animals fed WD-Corn on the contrary tend to a weakened disease progression in the described parameters. After 24 weeks feeding with WD-NTF and WD-Std, WD-Corn lead to a comparable steatohepatitis initiation by histomorphological changes and immune cell infiltration compared to WD-Std. Immune cell infiltration results in a significant increase in mRNA expression of the pro-inflammatory cytokines IL-6 and TNF-α, which is more pronounced in WD-NTF compared to WD-Std and WD-Corn. Interestingly the fat source has no impact on the composition of accumulating fat within liver tissue as determined by matrix-assisted laser desorption/ionization mass spectrometry imaging of multiple lipid classes. The described effects of different fat sources on the development of steatohepatitis finally resulted in variations in fibrosis development. Animals treated with WD-NTF displayed massive collagen accumulation, whereas WD-Corn even seems to protect from extracellular matrix deposition. Noteworthy, WD-Corn provokes massive histomorphological modifications in epididymal white adipose tissue (eWAT) and severe accumulation of extracellular matrix which are not apparent in WD-Std and WD-NTF treatment. Different fat sources in WD-Std contribute to strong steatohepatitis development in WT mice after 24 weeks treatment. Surprisingly, corn oil provokes histomorphological changes in eWAT tissue. Accordingly, both WD-NTF and WD-Corn appear suitable as alternative dietary treatment to replace "standard" WD-Std as a diet mouse model of steatohepatitis whereas WD-Corn leads to strong changes in eWAT morphology.

Dataset Information

Characterization of the CDAA Diet-Induced Non-alcoholic Steatohepatitis Model: Sex-Specific Differences in Inflammation, Fibrosis, and Cholesterol Metabolism in Middle-Aged Mice.

Background

Objectives

Methods and results

Conclusion

Publications

Characterization of the CDAA Diet-Induced Non-alcoholic Steatohepatitis Model: Sex-Specific Differences in Inflammation, Fibrosis, and Cholesterol Metabolism in Middle-Aged Mice.

Similar Datasets

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