Dominant-negative HNF1α mutant promotes liver steatosis and inflammation by regulating hepatic complement factor D
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ABSTRACT:
PROVIDER: PRJNA933171 | ENA |
REPOSITORIES: ENA
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Project description:Patients with HNF1A variants may develop liver steatosis, while the underlying mechanism is still unclear. Here, we established a mouse model carrying the dominant-negative HNF1α P291fsinsC mutation (hHNF1Amut/-) and found that the mutant mice developed liver steatosis spontaneously under the normal chow diet. Transcriptome analysis showed significant upregulation of Cfd and other genes related to innate immune response in the liver of hHNF1Amut/- mice. The changes in lipid metabolism and complement pathways were also confirmed by proteomics. We demonstrated that HNF1α inhibited CFD expression in hepatocytes, and the P291fsinsC mutant could reverse this inhibitory effect. Furthermore, the suppression of CFD with specific inhibitor or siRNAs reduced triglyceride levels in hepatocytes, suggesting that CFD regulated hepatocyte lipid deposition. Our results demonstrate that the HNF1α P291fsinsC mutant promotes hepatic steatosis and inflammation by upregulating CFD expression, and targeting CFD may delay the progression of nonalcoholic fatty liver disease.
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Project description:Individuals with hepatic steatosis often display several metabolic abnormalities including insulin resistance and muscle atrophy. Previously, we found that hepatic steatosis results in an altered hepatokine secretion profile, thereby inducing skeletal muscle insulin resistance via inter-organ crosstalk. In this study, we aimed to investigate whether the altered secretion profile in the state of hepatic steatosis also induces skeletal muscle atrophy via effects on muscle protein turnover. To investigate this, eight-week-old male C57BL/6J mice were fed a chow (4.5% fat) or a high-fat diet (HFD; 45% fat) for 12 weeks to induce hepatic steatosis, after which the livers were excised and cut into ~200 µm slices. Slices were cultured to collect secretion products (conditioned medium; CM). Differentiated L6-GLUT4myc myotubes were incubated with chow or HFD CM to measure glucose uptake. Differentiated C2C12 myotubes were incubated with chow or HFD CM to measure protein synthesis and breakdown, and gene expression via RNA sequencing. Furthermore, proteomics analysis was performed in chow and HFD CM. It was found that HFD CM caused insulin resistance in L6-GLUT4myc myotubes compared with chow CM, as indicated by a blunted insulin-stimulated increase in glucose uptake. Furthermore, protein breakdown was increased in C2C12 cells incubated with HFD CM, while there was no effect on protein synthesis. RNA profiling of C2C12 cells indicated that 197 genes were differentially expressed after incubation with HFD CM, compared with chow CM, and pathway analysis showed that pathways related to anatomical structure and function were enriched. Proteomic analysis of the CM showed that 32 proteins were differentially expressed in HFD CM compared with chow CM. Pathway enrichment analysis indicated that these proteins had important functions with respect to insulin-like Growth Factor transport and uptake, and affect post-translational processes, including protein folding, protein secretion and protein phosphorylation. In conclusion, the results of this study support the hypothesis that secretion products from the liver contribute to the development of muscle atrophy in individuals with hepatic steatosis.
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Project description:Background: Ginseng flower bud (GFB) is a part of ginseng with high content of ginsenosides, the known active components of ginseng. While the scientific data for the pharmacological activity of ginseng roots are accumulating, the therapeutic potential of GFB have been neglected. The current study aimed to examine the therapeutic effect of GFB on hepatic steatosis and to elucidate the underlying mechanisms. Methods: HepG2 cells treated with free fatty acids mixture and hepatocytes isolated from rats after 3 weeks of HFD feeding were used as in vitro models of hepatic steatosis for evaluation of anti-steatotic effect of GFB. The effect of GFB was further investigated in pathological conditions of hepatic steatosis induced by 12 weeks of HFD feeding in C57BL/6J mice. We performed systematical analyses on hepatic gene expression profiles in GFB treated mice. The effect of GFB on the expression profile of selected genes was validated by quantitative PCR. Results: GFB treatment markedly reduced oil red O stained lipid droplets and intracellular triglyceride levels in HepG2 cells and rat hepatocytes. In HFD-fed mice, GFB (500 mg/kg) treatment markedly reduced histological signs of hepatic steatosis and decreased hepatic triglyceride content by 34.1% compared to those of HFD. These changes by GFB treatment were accompanied by improved insulin signaling. Global gene expression analysis revealed that hepatic gene expression in the steatotic liver was reversed by GFB treatment, and the GFB-regulated genes are involved in immune process, insulin response and lipid storage. Conclusion: These findings provide a substantial evidence for the medicinal use of GFB in prevention or treatment of NAFLD through suppression of hepatic inflammation and fatty acid uptake while sensitizing hepatic insulin signaling
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