Dataset Information

Dietary Oxysterol, 7-Ketocholesterol Accelerates Hepatic Lipid Accumulation and Macrophage Infiltration in Obese Mice.

ABSTRACT: Non-alcoholic fatty liver disease is strongly associated with obese and type 2 diabetes. It has been reported that an oxidized cholesterol, 7-ketocholesterol (7KC), might cause inflammatory response in macrophages and plasma 7KC concentration were higher in patients with cardiovascular diseases or diabetes. Therefore, we have decided to test whether small amount of 7KC in diet might induce hepatic steatosis and inflammation in two types of obese models. We found that addition of 0.01% 7KC either in chow diet (CD, regular chow diet with 1% cholesterol) or western type diet (WD, high fat diet with 1% cholesterol) accelerated hepatic neutral lipid accumulation by Oil Red O staining. Importantly, by lipid extraction analysis, it has been recognized that triglyceride rather than cholesterol species was significantly accumulated in CD+7KC compared to CD as well as in WD+7KC compared to WD. Immunostaining revealed that macrophages infiltration was increased in CD+7KC compared to CD, and also in WD+7KC compared to WD. These phenotypes were accompanied by inducing inflammatory response and downregulating fatty acid oxidation. Furthermore, RNA sequence analysis demonstrated that 7KC reduced expression of genes which related to autophagy process. Levels of LC3-II protein were decreased in WD+7KC compared to WD. Similarly, we have confirmed the effect of 7KC on acceleration of steatohepatitis in db/db mice model. Collectively, our study has demonstrated that small amount of dietary 7KC contributed to accelerate hepatic steatosis and inflammation in obese mice models.

SUBMITTER: Chang J

PROVIDER: S-EPMC7989701 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Dietary Oxysterol, 7-Ketocholesterol Accelerates Hepatic Lipid Accumulation and Macrophage Infiltration in Obese Mice.

Chang Jiuyang J Koseki Masahiro M Saga Ayami A Kanno Kotaro K Higo Tomoaki T Okuzaki Daisuke D Okada Takeshi T Inui Hiroyasu H Tanaka Katsunao K Asaji Masumi M Zhu Yinghong Y Kamada Yoshihiro Y Ono Masafumi M Saibara Toshiji T Ichi Ikuyo I Ohama Tohru T Nishida Makoto M Yamashita Shizuya S Sakata Yasushi Y

Frontiers in endocrinology 20210310

Non-alcoholic fatty liver disease is strongly associated with obese and type 2 diabetes. It has been reported that an oxidized cholesterol, 7-ketocholesterol (7KC), might cause inflammatory response in macrophages and plasma 7KC concentration were higher in patients with cardiovascular diseases or diabetes. Therefore, we have decided to test whether small amount of 7KC in diet might induce hepatic steatosis and inflammation in two types of obese models. We found that addition of 0.01% 7KC either ...[more]

PMID: 33776901

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Project description:Background/aimsLiver lipid accumulation induced by high-fat diet (HFD) is an early onset process of non-alcoholic fatty liver diseases (NAFLD). Protein kinase A (PKA) is known to be involved in hepatic lipid metabolism. However, the role of PKA in NAFLD has not been well tested in vivo due to the lack of optimal PKA deficient mouse model.MethodsA novel PKA-specific inhibitor gene was conditionally overexpressed in mouse (PKAi mouse) liver using LoxP/Cre system. PKA activity in the liver extract was measured with a commercial assay kit. The PKAi and control mice of 8-week age, were subjected to HFD or chow diet (CD) for 2 months. Body weight, liver index, and triglyceride in the liver were measured. RNA sequencing was performed for the liver tissues and analyzed with Gene Ontology (GO) and pathway enrichment.ResultsPKAi-GFP protein was overexpressed in the liver and the PKA activation was significantly inhibited in the liver of PKAi mouse. When fed with CD, RNA sequencing revealed 56 up-regulated and 51 down-regulated genes in PKAi mice compared with control mice, which were mainly involved in lipid metabolism though no significant differences in the body weight, liver index, triglyceride accumulation were observed between PKAi and control mice. However, when fed with HFD for 2 months, the liver was enlarged more, and the accumulation of triglyceride in the liver was more severe in PKAi mice. When comparing the transcriptomes of CD-fed and HFD-fed control mice, GO enrichment showed that the genes down-regulated by HFD were mainly enriched in immune-related GO terms, and up-regulated genes were enriched in metabolism. When comparing the transcriptomes of CD-fed and HFD-fed PKAi mice, GO analysis showed that the down-regulated genes were enriched in metabolism, while the up-regulated genes were clustered in ER stress-related pathways. When comparing HFD-fed PKAi and HFD-fed control mice, the genes with lower expression level in PKAi mice were enriched in the lipoprotein synthesis, which might explain that more TG is accumulated in PKAi liver after HFD feeding.ConclusionsReduced PKA activity could be a factor promoting the TG accumulation in the liver and the development of NAFLD.

Project description:Background Obesity, which results from a caloric intake and energy expenditure imbalance, is highly prevalent worldwide. Cathepsin S (CTSS), which is a cysteine protease, is elevated in obesity and may regulate a variety of physiological processes. This study sought to investigate the functional role of CTSS in obesity. Methods Mice were administrated 60 mg/kg of RO5444101 in vivo and fed a high-fat diet (HFD) to induce obesity. The weights of the mice fed a normal-chow diet and a HFD were measured. The expression levels of total triglycerides (TG), total cholesterol (TC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and monocyte chemoattractant protein-1 (MCP-1) were assessed using appropriate corresponding assay kits. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to estimate the messenger ribonucleic acid (mRNA) expression of CTSS in the serum and the release of M1- and M2-type cytokines, and western blot was used to measure the phosphorylated-nuclear factor kappaB (NF-kappaB) p65 and NF-κB p65 proteins. The mRNA and protein expressions of sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FASN), leptin, and adiponectin were also evaluated by RT-qPCR and western blot. Further, hematoxylin and eosin (H&E), immunohistochemical, and red oil O staining were employed to detect the pathological changes of the epididymal white adipose tissue (eWAT), the macrophage infiltration in the eWAT, and lipid accumulation, respectively. Results We found that CTSS was elevated in the plasma, visceral adipose, and liver tissues of the obese mice. After the administration of 60 mg/kg of RO5444101, the weight of the obese mice decreased, insulin resistance was inhibited, and adipocyte formation was suppressed. The CTSS inhibitor also decreased the level of macrophage infiltration in the eWAT, MCP-1 expression, and the release of M1- and M2-type cytokines in the HFD-induced mice. The CTSS inhibitor appeared to improve the hepatic function parameters and lipid accumulation of the HFD-induced mice. The CTSS inhibitor also appeared to improve the inflammatory damage in the HFD-induced mice. Conclusions CTSS inhibitor helped to protect against HFD-induced adipogenesis, inflammatory infiltration, and hepatic lipid accumulation in obese mice.

Dataset Information

Dietary Oxysterol, 7-Ketocholesterol Accelerates Hepatic Lipid Accumulation and Macrophage Infiltration in Obese Mice.

Publications

Dietary Oxysterol, 7-Ketocholesterol Accelerates Hepatic Lipid Accumulation and Macrophage Infiltration in Obese Mice.

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