Proteomic analysis of neonatal mouse hearts shows PKA functions as a cardiomyocyte replication regulator.

The ability of the adult mammalian heart to regenerate can save the cardiac muscle from a loss of function caused by injury. Cardiomyocyte regeneration is a key aspect of research for the treatment of cardiovascular diseases. The mouse heart shows temporary regeneration in the first week after birth; thus, the newborn mouse heart is an ideal model to study heart muscle regeneration. In this study, proteomic analysis was used to investigate the differences in protein expression in the hearts of neonatal mice at days 1 (P1 group), 4 (P4 group), and 7 (P7 group). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed changes in several groups of proteins, including the protein kinase A (PKA) signaling pathway. Moreover, it was found that PKA inhibitors and agonists regulated cardiomyocyte replication in neonatal mouse hearts. These findings suggest that PKA may be a target for the regulation of the cardiomyocyte cell cycle.

LncRNA Nron deficiency protects mice from diet-induced adiposity and hepatic steatosis.

Obesity, as a worldwide healthcare problem, has attracted more and more attention. Here we identify a long non-coding RNA NRON, which is highly conserved across species, as an important regulator of glucose/lipid metabolism and whole-body energy expenditure. Depletion of Nron leads to metabolic benefits in DIO (diet-induced obesity) mice, including reduced body weight and fat mass, improved insulin sensitivity and serum lipid parameters, attenuated hepatic steatosis and enhanced adipose function. Mechanistically, Nron deletion improves hepatic lipid homeostasis via PER2/Rev-Erbα/FGF21 axis coupled with AMPK activation, and enhances adipose function via activating the process of triacylglycerol hydrolysis and fatty acid re-esterification (TAG/FA cycling) and coupled metabolic network. These interactive and integrative effects cooperatively account for a healthier metabolic phenotype in NKO (Nron knockout) mice. Genetic or pharmacological inhibition of Nron may have potential for future therapy of obesity.

Management of Rheumatoid Arthritis With a Digital Health Application: A Multicenter, Pragmatic Randomized Clinical Trial.

IMPORTANCE: Digital health applications have been shown to be effective in the management of chronic diseases with simple treatment targets. The potential clinical value of digital health applications in rheumatoid arthritis (RA) has not been well studied. OBJECTIVE: To investigate whether assessing patient-reported outcomes using digital health applications could result in disease control for patients with RA. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter, open-label randomized clinical trial in 22 tertiary hospitals across China. Eligible participants were adult patients with RA. Participants were enrolled from November 1, 2018, to May 28, 2019, with a 12-month follow-up. The statisticians and rheumatologists who assessed disease activity were blinded. Investigators and participants were not blind to group assignment. Analysis was conducted from October 2020 to May 2022. INTERVENTIONS: Participants were randomly assigned at a 1:1 ratio (block size of 4) to a smart system of disease management group (SSDM) or a conventional care control group. Upon the completion of the 6-month parallel comparison, patients in the conventional care control group were instructed to use the SSDM application for an extension of 6 months. MAIN OUTCOMES AND MEASURES: The primary outcome was the rate of patients with disease activity score in 28 joints using the C-reactive protein (DAS28-CRP) of 3.2 or less at month 6. RESULTS: Of 3374 participants screened, 2204 were randomized, and 2197 patients with RA (mean [SD] age, 50.5 [12.4] years; 1812 [82.5%] female) were enrolled. The study included 1099 participants in the SSDM group and 1098 participants in the control group. At month 6, the rate of patients with DAS28-CRP of 3.2 or less was 71.0% (780 of 1099 patients) in the SSDM group vs 64.5% (708 of 1098 patients) in the control group (difference between groups, 6.6%; 95% CI, 2.7% to 10.4%; P = .001). At month 12, the rate of patients with DAS28-CRP of 3.2 or less in the control group increased to a level (77.7%) that was comparable with that (78,2%) in the SSDM group (difference between groups, -0.2%; 95% CI, -3.9% to 3.4%; P = .90). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of RA, the use of a digital health application with patient-reported outcomes was associated with an increase in disease control rate. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03715595.

A rare concomitance of Wilson's disease and systemic lupus erythematosus in a teenage girl: a case report and literature review.

Background: Wilson's disease (WD) is an inherited disorder characterized by impaired biliary excretion of copper and excessive copper accumulation in multiple organs, primarily leading to hepatic, neurological, and psychiatric manifestations. The coexistence of WD and systemic lupus erythematosus (SLE) has rarely been reported, posing challenges in accurately diagnosing these two conditions because of overlapping clinical symptoms. Case presentation: We presented the case of a 17-year-old girl initially suspected of having SLE due to positive anti-nuclear antibodies and lupus anticoagulants, decreased platelet count, hypocomplementemia, and pleural effusion. However, the patient also exhibited an unusual manifestation of decompensated liver cirrhosis, which is not typical of SLE. Further investigation revealed low serum ceruloplasmin levels, high 24-h urine copper levels, the presence of Kayser-Fleischer rings, and a compound heterozygous mutation in the ATP7B gene, confirming the diagnosis of WD. Conclusion: The co-occurrence of WD and SLE poses a significant diagnostic challenge, often leading to misdiagnosis and delayed diagnosis. Therefore, in patients with well-controlled SLE presenting with unexplained liver fibrosis, neurological involvement, or psychiatric symptoms, it is crucial to consider the possibility of WD. However, further studies are required to elucidate the underlying pathophysiological mechanisms.

Attitudes toward COVID-19 Vaccination: A Survey of Chinese Patients with Rheumatic Diseases.

The coronavirus disease 2019 (COVID-19) pandemic has imposed enormous morbidity and mortality burdens. Patients with rheumatic diseases (RDs) are vulnerable to the COVID-19 infection, given their immunocompromised status. Ensuring acceptance of the COVID-19 vaccine is important and has attracted attention by health professionals. In this study, we designed an online cross-sectional survey that used an online questionnaire from 8 May 2021 to 4 October 2021. Attitudes toward the COVID-19 vaccination, personal information, current disease activity status, adverse events (AEs), and knowledge sources of vaccines were collected. Descriptive statistics, nonparametric tests, and ordinal logistic regression were used to analyze the data. A total of 1022 questionnaires were received, among which 70.2% (720/1022) of patients with RDs agreed to vaccination, while only 31.6% of patients were actually vaccinated. Male, employed, high-income patients and those with inactive disease showed a more positive attitude. Concerns of AEs and disease flare were the main factors affecting vaccination willingness. Only 29.6% (304/1022) of patients thought they had received enough information about the COVID-19 vaccine from their doctors. In conclusion, most patients with RDs in China intended to get vaccinated, although the vaccination rate in this particular population was low. Rheumatologists should take more responsibility in COVID-19 vaccination education of patients with RDs.

Prevalence and prognosis of molecularly defined familial hypercholesterolemia in patients with acute coronary syndrome.

Background: Familial hypercholesterolemia (FH) can elevate serum low-density lipoprotein cholesterol (LDL-C) levels, which can promote the progression of acute coronary syndrome (ACS). However, the effect of FH on the prognosis of ACS remains unclear. Methods: In this prospective cohort study, 223 patients with ACS having LDL-C ≥ 135.3 mg/dL (3.5 mmol/L) were enrolled and screened for FH using a multiple-gene FH panel. The diagnosis of FH was defined according to the ACMG/AMP criteria as carrying pathogenic or likely pathogenic variants. The clinical features of FH and the relationship of FH to the average 16.6-month risk of cardiovascular events (CVEs) were assessed. Results: The prevalence of molecularly defined FH in enrolled patients was 26.9%, and coronary artery lesions were more severe in patients with FH than in those without (Gensini score 66.0 vs. 28.0, respectively; P < 0.001). After lipid lowering, patients with FH still had significantly higher LDL-C levels at their last visit (73.5 ± 25.9 mg/dL vs. 84.7 ± 37.1 mg/dL; P = 0.013) compared with those without. FH increased the incidence of CVEs in patients with ACS [hazard ratio (HR): 3.058; 95% confidence interval (CI): 1.585-5.900; log-rank P < 0.001]. Conclusion: FH is associated with an increased risk of CVEs in ACS and is an independent risk factor for ACS. This study highlights the importance of genetic testing of FH-related gene mutations in patients with ACS.

Hypocomplementemia in primary Sjogren's syndrome: association with serological, clinical features, and outcome.

OBJECTIVE: The aim of the present study was to assess the clinical characteristic of hypocomplementemia (HC) in primary Sjogren's syndrome (pSS), and to address possible risk factors and the prognosis associated with HC in pSS patients. METHODS: pSS patients with HC in Hebei General Hospital from September 2016 to March 2019 were retrospectively analyzed and compared to those with normocomplementemia (NC). Logistic regression analysis was used to detect risk factors. RESULTS: Of the 333 patients with pSS, 84 patients (25.23%) were presented with HC at diagnosis. The presence of hyper-IgG and anti-Ro52 antibodies was significantly more common in patients with HC. In addition to systemic involvement, pSS patients with HC had more hematological, renal, and nervous system involvement, and received more immunosuppressant treatments than NC group (p < 0.05). ESSDAI score was significantly higher in patients with HC (p < 0.05). Multivariate logistic analysis indicated that leukopenia (OR = 2.23) and hyper-IgG (OR = 2.13) were independent risk factors for pSS with HC. In addition, profound CD16/CD56+ NK-cell lymphopenia was found in pSS-HC patients. More pSS patients developed SLE in the HC group than NC group (4.76% vs. 0.80%, p = 0.04) during the follow-up. CONCLUSION: HC was not an uncommon manifestation of pSS and had an independent association with the main clinical and immunological features. Patients with pSS-HC had an increased possibility to develop SLE that required more positive treatment with glucocorticoids and immunosuppressants. KEY POINTS: • Hypocomplementemia had an independent association with the main clinical and immunological features in primary Sjogren's syndrome patients. • ESSDAI score was significantly higher in patients with hypocomplementemia. • The pSS patients with hypocomplementemia had an increased possibility to develop SLE.

The role of long noncoding RNA Nron in atherosclerosis development and plaque stability.

The major clinical consequences of atherosclerosis such as myocardial infarction or stroke are because of thrombotic events associated with acute rupture or erosion of an unstable plaque. Here, we identify an lncRNA Noncoding Repressor of NFAT (Nron) as a critical regulator of atherosclerotic plaque stability. Nron overexpression (OE) in vascular smooth muscle cells (VSMC) induces a highly characteristic architecture of more-vulnerable plaques, while Nron knockdown (KD) suppresses the development of atherosclerosis and favors plaque stability. Mechanistically, Nron specifically binds to and negatively regulates NFATc3, thus inhibiting the proliferation and promoting the apoptosis of VSMCs. Moreover, we also provide evidence that Nron increases the production and secretion of VEGFA from VSMCs, which functions as a paracrine factor to enhance intra-plaque angiogenesis. All of these effects contribute to plaque instability. Genetic or pharmacological inhibition of Nron may have potential for future therapy of atherosclerosis.

Interstitial lung disease in Primary Sjögren's syndrome.

BACKGROUND: Interstitial lung disease (ILD) may cause life-threatening complications of primary Sjogren's syndrome (pSS), and has a poor prognosis in terms of survival and quality of life. To date, few studies have investigated the risk factors for ILD detected by high-resolution computed tomography (HRCT) in pSS patients with or without respiratory symptoms. METHODS: Data of 333 patients with newly diagnosed pSS were retrospectively analysed. Interstitial lung disease involvement was defined as typical abnormalities on HRCT and/or pulmonary function tests. Multivariate regression model was used to evaluate the association between interstitial lung disease and pSS characteristics. RESULTS: Sixty-six patients (19.82%) were diagnosed with pSS-ILD. Ground glass opacities (87.88%) and septal/sub pleural lines (81.82%) were most frequent. Based on pulmonary high-resolution computed tomography, patients were divided into nonspecific (n = 42), usual (n = 20), lymphocytic interstitial pneumonia (n = 3) and cryptogenic organising pneumonia (n = 1) groups. There was a strong association between erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) and the HRCT-score. Pulmonary function tests revealed impaired diffusion capacity for carbon monoxide and total lung capacity, and coexistence of small airway lesions in pSS-interstitial lung disease. On logistic regression analysis, age, Raynaud's phenomenon, lymphopenia, cough, dyspnoea and rampant dental caries were risk factors associated with pSS-interstitial lung disease. CONCLUSIONS: Interstitial lung disease involvement in pSS is a common clinical occurrence. The clinical manifestation is nonspecific and variable; Raynaud's phenomenon and lymphopenia may predict its onset. pSS patients with advanced age, dry cough and dyspnoea should be systematically evaluated for ILD involvement and managed according to their symptoms.

Multifunctional MOF-based probes for efficient detection and discrimination of Pb2+, Fe3+ and Cr2O72-/CrO42.

Developing metal-organic framework (MOF)-based fluorescent probes for efficient detection and discrimination of polluting ions in groundwater is vital for environmental protection and human health. In this paper, we prepared two luminescence-active transition MOFs, namely, Zn-MOF and Cd-MOF, and conducted sensing experiments. The results show that they both exhibit multiple-target detection for Fe3+, Pb2+ and Cr(VI) with high sensitivity, good anti-interference ability and good recyclability even with different frameworks. In addition, Eu3+-incorporated samples, Eu3+@MOFs, with dual-emission have been fabricated via efficient encapsulation of Eu3+ ions into the MOF host. As expected, Eu3+@MOF hybrids also act as multi-target and self-calibrated probes to selectively detect Fe3+ and Cr(VI) ions. However, the quenching efficiencies of the original MOFs towards Fe3+ are higher than those of Eu3+@MOFs. Thus, we could differentiate Fe3+, Pb2+ and Cr(VI) ions by comparing the changes of fluorescence emission between Eu3+@MOFs and the original MOFs. The recognition mechanism may be attributed to the competitive energy absorption between MOFs or Eu3+@MOFs and the analytes.

Integrated Genome and Transcriptome Sequencing to Solve a Neuromuscular Puzzle: Miyoshi Muscular Dystrophy and Early Onset Primary Dystonia in Siblings of the Same Family.

BACKGROUND: Neuromuscular disorders (NMD), many of which are hereditary, affect muscular function. Due to advances in high-throughput sequencing technologies, the diagnosis of hereditary NMDs has dramatically improved in recent years. METHODS AND RESULTS: In this study, we report an family with two siblings exhibiting two different NMD, Miyoshi muscular dystrophy (MMD) and early onset primary dystonia (EOPD). Whole exome sequencing (WES) identified a novel monoallelic frameshift deletion mutation (dysferlin: c.4404delC/p.I1469Sfs∗17) in the Dysferlin gene in the index patient who suffered from MMD. This deletion was inherited from his unaffected father and was carried by his younger sister with EOPD. However, immunostaining staining revealed an absence of dysferlin expression in the proband's muscle tissue and thus suggested the presence of the second underlying mutant allele in dysferlin. Using integrated RNA sequencing (RNA-seq) and whole genome sequencing (WGS) of muscle tissue, a novel deep intronic mutation in dysferlin (dysferlin: c.5341-415A > G) was discovered in the index patient. This mutation caused aberrant mRNA splicing and inclusion of an additional pseudoexon (PE) which we termed PE48.1. This PE was inherited from his unaffected mother. PE48.1 inclusion altered the Dysferlin sequence, causing premature termination of translation. CONCLUSION: Using integrated genome and transcriptome sequencing, we discovered hereditary MMD and EOPD affecting two siblings of same family. Our results added further weight to the combined use of RNA-seq and WGS as an important method for detection of deep intronic gene mutations, and suggest that integrated sequencing assays are an effective strategy for the diagnosis of hereditary NMDs.

Outcome of mitral valve repair or replacement for non-ischemic mitral regurgitation: a systematic review and meta-analysis.

BACKGROUND: Mitral regurgitation (MR) is a rather common valvular heart disease. The aim of this systematic review and meta-analysis was to compare the outcomes, and complications of mitral valve (MV) replacement with surgical MV repair of non-ischemic MR (NIMR) METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched until October, 2020. Studies were eligible for inclusion if they included patients with MR and reported early (30-day or in-hospital) or late all-cause mortality. For each study, data on all-cause mortality and incidence of reoperation and operative complications in both groups were used to generate odds ratios (ORs) or hazard ratios (HRs). This study is registered with PROSPERO, CRD42018089608. RESULTS: The literature search yielded 4834 studies, of which 20 studies, including a total of 21,898 patients with NIMR, were included. The pooled analysis showed that lower age, less female inclusion and incident of hypertension, significantly higher rates of diabetes and atrial fibrillation in the MV replacement group than MV repair group. No significant differences in the rates of pre-operative left ventricle ejection fraction (LVEF) and heart failure were observed between groups. The number of patients in the MV repair group was lower than in the MV replacement group. We found that there were significantly increased risks of mortality associated with replacement of MR. Moreover, the rate of re-operation and post-operative MR in the MV repair group was lower than in the MV replacement group. CONCLUSIONS: In patients with NIMR, MV repair achieves higher survival and leads to fewer complications than surgical MV replacement. In light of these results, we suggest that MV repair surgery should be a priority for NIMR patients.

Resveratrol affects the expression of uric acid transporter by improving inflammation.

Resveratrol (RSV), a polyphenol, non­flavonoid plant­derived antitoxin, ameliorates hyperuricemia and kidney inflammation. The present study aimed to establish a model of high­fat diet (HFD)­induced insulin resistance (IR) and to determine the specific mechanism of RSV to improve kidney inflammation and reduce uric acid (UA). C57BL/6J mice were fed a HFD for 12 weeks and their glucose tolerance was evaluated by intraperitoneal glucose tolerance testing. The mice were then administered RSV for 6 weeks, and blood and kidney samples were collected. Serum UA and insulin concentrations were determined using ELISA kits. Hematoxylin and eosin, periodic acid­Schiff and Masson staining were performed to observe the pathological changes of the kidney, and electron microscopy was used to observe changes in the kidney ultrastructure. The renal concentrations of interleukin (IL)­6, IL­18, IL­1ß and tumor necrosis factor­α (TNF­α) were measured using ELISA kits, and western blotting evaluated changes in the protein expression levels of various indicators. RSV significantly ameliorated HFD­induced IR and reduced blood UA levels. Long­term IR can lead to lipid deposition, glycogen accumulation, inflammatory damage and fibrotic changes in the kidney of mice. This leads to a significant increase in the expression of UA transport­related proteins, an increase in UA reabsorption and an increase in blood UA levels. Notably, RSV intervention was able to reverse this process. The effect of RSV may be achieved by inhibiting the NOD­like receptor family, pyrin domain­containing 3 (NLRP3) inflammasome and Toll­like receptor 4 (TLR4)/myeloid differentiation factor 88/nuclear factor­κB signaling pathway. In conclusion, RSV may improve kidney inflammation through TLR4 and NLRP3 signaling pathways, and reduce the expression of UA transporter proteins in the kidney of insulin­resistant mice, thereby reducing blood UA levels.

Clinical features and risk factors of Raynaud's phenomenon in primary Sjögren's syndrome.

OBJECTIVE: The aim at the current study was to investigate the clinical characteristics and risk factors of Raynaud's phenomenon (RP) in patients with primary Sjögren's syndrome (pSS). METHODS: Retrospective analysis of the medical records of 333 new-onset pSS patients was performed. Demographic, clinical, and serological data were compared between individuals with and without RP. Logistic regression analysis was used to identify risk factors. RESULTS: RP was present in 11.41% of the pSS patients. pSS-RP patients were younger (49.74±14.56 years vs. 54.46±13.20 years, p=0.04) and exhibited higher disease activity (11 [5.75-15] vs. 7 [4-12], p=0.03) than those without. The prevalence of lung involvement was significantly higher in pSS patients with RP (60.53% vs. 17.29%; p<0.001). A significantly higher proportion of patients with pSS-RP tested positive about antinuclear (ANA), anti-RNP, and anti-centromere antibodies (ACA) compared to those without (p=0.003, <0.001, and 0.01, respectively). Multivariate analysis identified lung involvement (odds ratio [OR]=8.81, 95% confidence interval [CI] 2.02-38.47; p=0.04), anti-RNP positive status (OR=79.41, 95% CI 12.57-501.78; p<0.0001), as well as ACA (OR=13.17, 95% CI 2.60-66.72; p=0.002) as prognostic factors for pSS-RP. CONCLUSION: The presence of RP defined a subset of pSS with a unique phenotype, manifesting as increased lung involvement and a higher frequency of anti-RNP antibodies and ACA, as well as greater disease activity. These results suggest that RP has clinical and prognostic value of pSS patients. Further prospective studies with a larger number of subjects are warranted to confirm our findings and assess the prognostic and treatment implications of RP in pSS patients. Key Points • Raynaud's phenomenon (RP) was present in 38 (11.41%) of 333 patients with primary Sjögren's syndrome (pSS), with patients with RP exhibiting a younger age and higher disease activity. • The presence of RP indicates a subset of pSS with a unique phenotype, with manifestations including increased lung involvement and a higher frequency of anti-RNP antibodies and anti-centromere antibodies. • Patients with pSS and RP need close follow-up and long-term observation (including assessment of microangiopathy), with specific attention paid to the possible development of clinical features of systemic sclerosis.

Involuntary movement in stiff-person syndrome with amphiphysin antibodies: A case report.

RATIONALE: Stiff-person syndrome (SPS) is a rare neurological immune disorder characterized by progressive axial and proximal limb muscle rigidity, stiffness, and painful muscle spasms. Amphiphysin antibodies are positive in approximately 5% of SPS patients. To date, there have been no relevant reports on involuntary movement in cases of SPS with amphiphysin antibodies. PATIENT CONCERNS: We describe the case of a 69-year-old man with a 2-year history of progressive stiffness in the neck, bilateral shoulders, and chest muscles, and a more-than-a-year history of dyspnea accompanied by mandibular involuntary movement. The patient was a vegetarian and had good health in the past. The family's medical history was unremarkable. DIAGNOSES: He was diagnosed with SPS based on the progressive muscle stiffness, the amphiphysin antibody seropositivity, the continuous motor activity on electromyography, and the effective treatment with benzodiazepines. INTERVENTIONS: The patient was orally administered clonazepam and baclofen, and corticosteroid IV followed by prednisone orally. OUTCOMES: In the hospital, after treatment with methylprednisolone, clonazepam, and baclofen, the patient's rigidity, stiffness, and dyspnea significantly improved. The involuntary movement of the mandible persisted throughout the treatment process. Currently, under oral treatment with baclofen and clonazepam, the patient's symptoms of muscle stiffness and dyspnea exist, and follow-up is continued. LESSONS: We report a rare and novel case of involuntary movement in SPS with amphiphysin antibodies. The present report explores the relationship between SPS and involuntary movement and expands the spectrum of clinical manifestations of SPS.

E3 Ligase FBXW2 Is a New Therapeutic Target in Obesity and Atherosclerosis.

Chronic low-grade inflammation orchestrated by macrophages plays a critical role in metabolic chronic diseases, like obesity and atherosclerosis. However, the underlying mechanism remains to be elucidated. Here, the E3 ubiquitin ligase F-box/WD Repeat-Containing Protein 2 (FBXW2), the substrate-binding subunit of E3 ubiquitin ligase SCF (a complex of FBXW2, SKP1, and cullin-1), as an inflammatory mediator in macrophages, is identified. Myeloid-specific FBXW2 gene deficiency improves both obesity-associated with insulin resistance and atherosclerosis in murine models. The beneficial effects by FBXW2 knockout are accompanied by decreased proinflammatory responses and macrophage infiltration in the microenvironment. Mechanistically, it is identified that KH-type splicing regulatory protein (KSRP) is a new bona fide ubiquitin substrate of SCFFBXW2. Inhibition of KSRP prevents FBXW2-deficient macrophages from exerting a protective effect on inflammatory reactions, insulin resistance and plaque formation. Furthermore, it is demonstrated that the C-terminus (P3) of FBXW2 competitively ablates the function of FBXW2 in KSRP degradation and serves as an effective inhibitor of obesity and atherogenesis progression. Thus, the data strongly suggest that SCFFBXW2 is an important mediator in the context of metabolic diseases. The development of FBXW2 (P3)-mimicking inhibitors and small-molecular drugs specifically abrogating KSRP ubiquitination-dependent inflammatory responses are viable approaches for obesity and atherosclerosis treatment.

Yin and Yang Regulation of Liver X Receptor α Signaling Control of Cholesterol Metabolism by Poly(ADP-ribose) polymerase 1.

Liver X receptor α (LXRα) controls a set of key genes involved in cholesterol metabolism. However, the molecular mechanism of this regulation remains unknown. The regulatory role of poly(ADP-ribose) polymerase 1 (PARP1) in cholesterol metabolism in the liver was examined. Activation of PARP1 in the liver suppressed LXRα sensing and prevented upregulation of genes involved in HCD-induced cholesterol disposal. Mechanistically, LXRα was poly(ADP-ribosyl)ated by activated PARP1, which decreased DNA binding capacity of LXRα, thus preventing its recruitment to the target promoter. Intriguingly, we found that unactivated PARP1 was indispensable for LXRα transactivation and target expression. Further exploration identified unactivated PARP1 as an essential component of the LXRα-promoter complex. Taken together, the results indicate that activated PARP1 suppresses LXRα activation through poly(ADP-ribosyl)ation, while unactivated PARP1 promotes LXRα activation through physical interaction. PARP1 is a pivotal regulator of LXRα signaling and cholesterol metabolism in the liver.

Targeting NFATc4 attenuates non-alcoholic steatohepatitis in mice.

BACKGROUND & AIMS: The nuclear factor of activated T-cells (NFAT) family was first recognised to play an important role in the differentiation of T cells, but has since been shown to regulate multiple pathophysiological processes. However, whether it is involved in the pathogenesis of non-alcoholic steatohepatitis (NASH) remains unknown. METHODS: Hepatic NFATc expression and localisation were analysed in C57BL/6 mice on a methionine-choline-deficient diet, as well as in samples from non-alcoholic fatty liver disease patients. Gain- or loss-of-function approaches were used to investigate the role of NFATc4 in NASH. RESULTS: NFATc4 translocates from the cytoplasm to the nucleus in hepatocytes of both humans and rodents with NASH. NFATc4 knockdown resulted in decreased hepatic steatosis, inflammation, and fibrosis during NASH progression. Mechanistically, we found that activated NFATc4 directly bound to peroxisome proliferator-activated receptor α (PPARα) in the nucleus and negatively regulated its transcriptional activity, thereby impairing the hepatic fatty acid oxidation pathway and increasing lipid deposition in the liver. Moreover, NFATc4 activation increased the production and secretion of osteopontin (OPN) from hepatocytes, which subsequently enhanced the macrophage-mediated inflammatory response and hepatic stellate cell-mediated fibrosis progression via paracrine signalling. CONCLUSIONS: Hepatic NFATc4 activation accelerates the progression of NASH by suppressing PPARα signalling and increasing OPN expression. Genetic or pharmacological inhibition of NFATc4 may have potential for future therapy of NASH. LAY SUMMARY: NFATc4 is activated in the non-alcoholic steatohepatitis of mice and patients. Inhibition of NFATc4 activation alleviates lipid deposition, inflammatory response, and fibrosis progression in the liver.