The Role of Chaperone-Mediated Autophagy in Hepatitis C Virus-Induced Pathogenesis

Lysosome incorporate and degrade proteins in a process known as autophagy. There are three types of autophagy; macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Although autophagy is considered a nonselective degradation process, CMA is known as a selective degradation pathway. All proteins internalized in the lysosome via CMA contain a pentapeptide KFERQ-motif, also known as a CMA-targeting motif, which is necessary for selectivity. CMA directly delivers a substrate protein into the lysosome lumen using the cytosolic chaperone HSC70 and the lysosomal receptor LAMP-2A for degradation. Hepatitis C virus (HCV) NS5A protein interacts with hepatocyte-nuclear factor 1α (HNF-1α) together with HSC70 and promotes the lysosomal degradation of HNF-1α via CMA, resulting in HCV-induced pathogenesis. HCV NS5A promotes recruitment of HSC70 to the substrate protein HNF-1α. HCV NS5A plays a crucial role in HCV-induced CMA. Further investigations of HCV NS5A-interacting proteins containing CMA-targeting motifs may help to elucidate HCV-induced pathogenesis.

Hepatocyte Nuclear Factor -1α stimulates cervical cancer cells to migrate and invade through regulating pyruvate kinase L/R

This study was aimed to analyze the role of hepatocyte nuclear factor -1α (HNF-1α) in regulating migrative and invasive potentials in cervical cancer via the involvement of pyruvate kinase L/R (PKLR). The expression of HNF-1α and PKLR in cervical cancer tissues classified by tumor size and FIGO (Federation International of Gynecology and Obstetrics) stage were detected by qRT-PCR. The expression correlation between HNF-1α and PKLR in cervical cancer tissues was analyzed by Pearson correlation test. After intervening HNF-1α and PKLR levels in SiHa and Hela cells, their migratory and invasive abilities were examined by the Transwell assay. HNF-1α was upregulated in cervical cancer tissues, particularly those with large tumor size or advanced FIGO stage. PKLR was highly expressed in cervical cancer tissues as well, presenting a positive correlation with the HNF-1α level. Knockdown of HNF-1α attenuated migratory and invasive abilities in SiHa cells, whereas overexpression of HNF-1α enhanced migratory and invasive abilities in SiHa cells. PKLR was able to abolish the regulatory effects of HNF-1α on cervical cancer metastasis. HNF-1α and PKLR synergistically promote cervical cancer to migrate and invade.

Lunasin Improves the LDL-C Lowering Efficacy of Simvastatin via Inhibiting PCSK9 Expression in Hepatocytes and ApoE−/− Mice

Statins are the most popular therapeutic drugs to lower plasma low density lipoprotein cholesterol (LDL-C) synthesis by competitively inhibiting hydroxyl-3-methyl-glutaryl-CoA (HMG-CoA) reductase and up-regulating the hepatic low density lipoprotein receptor (LDLR). However, the concomitant up-regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) by statin attenuates its cholesterol lowering efficacy. Lunasin, a soybean derived 43-amino acid polypeptide, has been previously shown to functionally enhance LDL uptake via down-regulating PCSK9 and up-regulating LDLR in hepatocytes and mice. Herein, we investigated the LDL-C lowering efficacy of simvastatin combined with lunasin. In HepG2 cells, after co-treatment with 1 μM simvastatin and 5 μM lunasin for 24 h, the up-regulation of PCSK9 by simvastatin was effectively counteracted by lunasin via down-regulating hepatocyte nuclear factor 1α (HNF-1α), and the functional LDL uptake was additively enhanced. Additionally, after combined therapy with simvastatin and lunasin for four weeks, ApoE−/− mice had significantly lower PCSK9 and higher LDLR levels in hepatic tissues and remarkably reduced plasma concentrations of total cholesterol (TC) and LDL-C, as compared to each monotherapy. Conclusively, lunasin significantly improved the LDL-C lowering efficacy of simvastatin by counteracting simvastatin induced elevation of PCSK9 in hepatocytes and ApoE−/− mice. Simvastatin combined with lunasin could be a novel regimen for hypercholesterolemia treatment.

Hepatocyte Nuclear Factor 1α-Mutated Hepatocellular Adenomas: An Atypical Presentation

Hepatocellular adenomas (HCAs) are rare benign monoclonal hepatic tumors that commonly occur in females (3–4 per 100,000 women) due to the use of oral contraceptives, its primary risk factor. Recently, HCAs have been classified into 4 distinct subtypes according to genotypic and phenotypic characteristics and clinical features: inflammatory HCA (40–50%), which are hypervascular with marked peliosis and a tendency to bleed; hepatocyte nuclear factor 1α (HNF1A)-mutated HCA (H-HCA, 30–40%) that are diffusely steatotic and rarely undergo malignant transformation; β-catenin activated HCA (10–15%), which frequently undergo malignant transformation and may seem hepatocellular carcinoma on imaging; and unclassified HCA (10–25%). In this study, we report the case of a 23-year-old female oral contraceptive user with H-HCA. Usually, H-HCA is considered to be nonsevere in most cases and often requires outpatient follow-up. However, in this case, the injury had substantially increased in volume and evolved with a major bleeding frame, which was an unusual finding for this subtype of adenoma. The therapeutic used for this patient was a laparoscopic left hepatic segmentectomy. Thus, the choice of treatment to be performed in a patient with H-HCA can depend on the tumor size (>5 cm), the outcome of previous bleeding, and the risk of bleeding recurrence.

Regulation of PDZ domain-containing 1 (PDZK1) expression by hepatocyte nuclear factor-1α (HNF1α) in human kidney

In the renal proximal tubule the secretion and reabsorption of glomerularly filtrated compounds is realized by a functional network of uptake and efflux transporters. The activity and localization of several transporters expressed at the apical tubular membrane are regulated by the membrane-associated protein PDZ domain-containing 1 (PDZK1). We aimed to characterize the transcriptional regulation of this modulator of renal transport. Coexpression analyses of PDZK1 and putative regulators were performed using human kidney samples. Protein and mRNA expression of PDZK1 in renal proximal tubule epithelial cells after adenoviral transfer and siRNA knockdown of transcription factor hepatocyte nuclear factor-1α (HNF1α) was assessed by quantitative real-time PCR and Western blot analysis. Transactivation of the PDZK1 promoter was quantified in cell-based reporter gene assays. Subsequently, the binding of HNF1α to the PDZK1 promoter was verified by in silico analyses and chromatin immunoprecipitation assay. HNF1α positively regulated the promoter activity of PDZK1. Adenoviral overexpression of HNF1α in renal proximal tubule epithelial cells (RPTEC) increased PDZK1 mRNA and protein expression, whereas siRNA knockdown of HNF1α resulted in decreased expression of PDZK1. Our results show that HNF1α, which has previously been described as a modulator of several transporters of the renal transportosome, is also a key determinant of PDZK1 transcription.