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Nicotinic alpha-7 acetylcholine receptor deficiency exacerbates hepatic inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis.

ABSTRACT: AIMS/INTRODUCTION:Non-alcoholic steatohepatitis (NASH), which occurs in association with insulin resistance and hepatic fat accumulation, is characterized by chronic liver injury and fibrosis. NASH onset and progression is closely related to hepatic inflammation, which is partly regulated by the vagus nerve through the ?7 nicotinic acetylcholine receptor (?7nAchR). Hepatic ?7nAchR action is impeded in obesity and insulin resistance. In the present study, using ?7nAchR knockout (?7KO) mice, we elucidated the effect of ?7nAchR deficiency on NASH-related inflammation and fibrosis. MATERIALS AND METHODS:?7KO mice were fed an atherogenic high-fat diet (AD) for 32 weeks or methionine/choline-deficient diet (MCD) for 6 weeks, both of which induce NASH. Mice were then examined for the degree of NASH-related inflammation and fibrosis by hepatic gene expression analysis and Sirius red histological staining. RESULTS:Hepatic triglyceride accumulation and elevated plasma transaminase levels were observed in both AD and MCD mice, but the plasma transaminase level increase was higher in ?7KO mice than in control mice. ?7KO mice fed an AD showed significant upregulation of the Col1a1 gene encoding alpha-1 type I collagen, which is involved in liver fibrosis, and the Ccl2 gene encoding C-C motif chemokine ligand 2, a pro-inflammatory chemokine; ?7KO mice fed an MCD had significant upregulation of the Col1a1 gene and the Tnf gene, an inflammatory cytokine. Histological analysis showed that AD and MCD exacerbated liver fibrosis in ?7KO mice. CONCLUSIONS:The results of this study suggest that ?7nAchR deficiency exacerbates hepatic inflammation and fibrosis in a diet-induced mouse model of NASH.

SUBMITTER: Kimura K

PROVIDER: S-EPMC6497582 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Nicotinic alpha-7 acetylcholine receptor deficiency exacerbates hepatic inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis.

Kimura Kumi K Inaba Yuka Y Watanabe Hitoshi H Matsukawa Toshiya T Matsumoto Michihiro M Inoue Hiroshi H

Journal of diabetes investigation 20181216 3

<h4>Aims/introduction</h4>Non-alcoholic steatohepatitis (NASH), which occurs in association with insulin resistance and hepatic fat accumulation, is characterized by chronic liver injury and fibrosis. NASH onset and progression is closely related to hepatic inflammation, which is partly regulated by the vagus nerve through the α7 nicotinic acetylcholine receptor (α7nAchR). Hepatic α7nAchR action is impeded in obesity and insulin resistance. In the present study, using α7nAchR knockout (α7KO) mic ...[more]

PMID: 30369082

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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:BackgroundHepatic fibrosis is a widespread disease worldwide. Millions of people lose their lives due to hepatic fibrosis every year. The main causes of hepatic fibrosis include viral infection, alcoholism, and obesity. Many studies have been conducted on the single factors that cause hepatic fibrosis; however, no studies have examined whether hepatic fibrosis caused by multiple factors has concomitant expression molecules and signaling pathways. In this study, we sought to analyze the common differentially expressed messenger ribonucleic acids (mRNAs) of hepatic fibrosis caused by different factors, including hepatitis B virus (HBV) hepatic fibrosis, alcoholic hepatic fibrosis, and non-alcoholic hepatic fibrosis, and identify potential preventive and therapeutic targets.MethodsThe GSE171294, GSE142530, and GSE126848 datasets from the Gene Expression Omnibus (GEO) public database were used in this study. A |log fold change| >0.5 and a P value <0.05 were defined as differentially expressed mRNAs via R software screening. To further screen the target mRNAs, the differential mRNAs were subjected to a functional enrichment analysis based on the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Finally, the relationships between differentially expressed mRNA-encoded proteins were analyzed by a protein-protein interaction (PPI) analysis.ResultsA total of 54 differentially expressed mRNAs were identified. The KEGG analysis showed that the functions of different mRNAs mainly focused on Gonadotropin Releasing Hormone (GnRH) secretion, bile secretion and insulin secretion. The GO enrichment analysis showed that the differential mRNAs were mainly present in the cytoplasmic membrane region and exerted biological functions, such as activating channels and binding proteins by regulating biological processes (BPs), such as cells, cytoskeleton and heparin. The PPI network analysis revealed 16 nodes with 12 pairs of interactions. The 16 critical nodes included BCL6, CD4, CD24, IL32, CALD1, TRAF3, SOX9, KANSL3, MRGBP, PKD2, PKHD1, SYT1, ANXA4, KCNMA1, KCNN2, and CACNA1H.ConclusionsKCNN2, CD4, CD24, BCL6, KCNMA1, and other molecules obtained by the bioinformatics analysis of the RNA-sequencing data can be used as new research targets for hepatic fibrosis induced by different causes. Our findings could provide novel ideas for the treatment of hepatic fibrosis.

Project description:Background and aimsThe augmenter of liver regeneration (ALR) protein is critical for lipid homeostasis and mitochondrial function. We investigated high-fat/high-carbohydrate (HF/HC) diet-induced nonalcoholic fatty liver disease (NAFLD) in wild-type (WT), hepatocyte-specific ALR-knockout (ALR-H-KO), and ALR-heterozygous (ALR-H-HET) mice. ALR was measured in serum of human nonalcoholic steatohepatitis (NASH) and NASH-induced cirrhosis (serum and liver).Approach and resultsHF/HC feeding decreased ALR expression in all groups of mice. The otherwise normal ALR-H-HET mice gained more weight and steatosis than WT mice when challenged metabolically with the HF/HC diet; ALR-H-KO mice gained the least weight and had the least steatosis. These findings were consistent with correspondingly increased triglycerides and cholesterol and altered expression of carnitine palmitoyltransferase 1a, sterol regulatory element-binding protein, acetyl coenzyme A carboxylase, and fatty acid synthase. All HF/HC-fed mice developed insulin resistance, the magnitude being lower in ALR-H-KO mice. HF/HC-fed ALR-H-HET mice were more resistant to glucose challenge than WT or ALR-H-KO mice. The frequency of tumor necrosis factor alpha-producing, interleukin 6 (IL6)-producing, and IL17-producing cells was greater in ALR-H-KO than ALR-H-HET and lowest in WT mice. HF/HC feeding did not increase their number in ALR-H-KO mice, and the increase in ALR-H-HET was greater than that in WT mice except for IL17 cells. Cluster of differentiation 25-positive (CD25+ ) forkhead box P3-positive CD4+ regulatory T-cell frequency was lower in ALR-H-HET than WT mice and further reduced in ALR-H-KO mice; HF/HC reduced regulatory T-cell frequency only in WT mice. HF/HC-fed ALR-H-HET, but not WT, mice developed fibrosis; and ALR-H-KO mice progressed to cirrhosis. White adipose tissue of HF/HC-fed ALR-deficient mice developed strong inflammation, indicating bidirectional interactions with the liver. Hepatic and serum ALR levels were significantly reduced in patients with NASH-cirrhosis. Serum ALR was also significantly lower in patients with NASH.ConclusionsHepatic ALR deficiency may be a critical predisposing factor for aggressive NAFLD progression.

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Nicotinic alpha-7 acetylcholine receptor deficiency exacerbates hepatic inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis.

Publications

Nicotinic alpha-7 acetylcholine receptor deficiency exacerbates hepatic inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis.

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