Biglycan promotes hepatic fibrosis through activating heat shock protein 47.

BACKGROUND: Biglycan (BGN) is a small leucine-rich proteoglycan that participates in the production of excess extracellular matrix (ECM) and is related to fibrosis in many organs. However, the role of BGN in liver fibrosis remains poorly understood. This study aimed to investigate the role and mechanism of BGN in liver fibrosis. METHODS: Human liver samples, Bgn-/0 (BGN KO) mice and a human LX-2 hepatic stellate cells (HSCs) model were applied for the study of experimental fibrosis. GEO data and single-cell RNA-seq data of human liver tissue were analysed as a bioinformatic approach. Coimmunoprecipitation, immunofluorescence staining, western blotting and qRT-PCR were conducted to identify the regulatory effects of BGN on heat shock protein 47 (HSP47) expression and liver fibrosis. RESULTS: We observed that hepatic BGN expression was significantly increased in patients with fibrosis and in a mouse model of liver fibrosis. Genetic deletion of BGN disrupted TGF-ß1 pathway signalling and alleviated liver fibrosis in mice administered carbon tetrachloride (CCl4 ). siRNA-mediated knockdown of BGN significantly reduced TGF-ß1-induced ECM deposition and fibroblastic activation in LX-2 cells. Mechanistically, BGN directly interacted with and positively regulated the collagen synthesis chaperon protein HSP47. Rescue experiments showed that BGN promoted hepatic fibrosis by regulating ECM deposition and HSC activation by positively regulating HSP47. CONCLUSION: Our data indicate that BGN promotes hepatic fibrosis by regulating ECM deposition and HSC activation through an HSP47-dependent mechanism. BGN may be a new biomarker of hepatic fibrosis and a novel target for disease prevention and treatment.

Low serum vitamin D concentrations are associated with obese but not lean NAFLD: a cross-sectional study.

BACKGROUND: A low serum vitamin D concentration has been reported to be associated with an increased risk of non-alcoholic fatty liver disease (NAFLD); however, whether lean or obese individuals show a similar association between vitamin D and NAFLD remains speculative. This study aimed to explore the relationship between serum vitamin D concentration and NAFLD in lean and obese Chinese adults. METHODS: This cross-sectional study included 2538 participants (1360 men and 1178 women) who underwent health checkups at the First Affiliated Hospital, Zhejiang University School of Medicine in 2019. NAFLD was diagnosed by liver ultrasound excluding other causes. The association of serum vitamin D concentration with NAFLD was analyzed in lean and obese participants. RESULTS: The overall prevalence of NAFLD was 33.61% (13.10% in lean and 53.32% in obese) in this study population. The serum vitamin D levels of obese NAFLD patients were lower than those of obese NAFLD-free controls. However, the serum vitamin D levels of lean NAFLD patients were comparable to those of lean NAFLD-free controls. Serum vitamin D level was negatively correlated with the prevalence of NAFLD in obese but not lean participants. Serum vitamin D level was independently associated with the risk of NAFLD in obese participants, with an adjusted odds ratio (95% CI) of 0.987 (0.981-0.993). However, serum vitamin D level was not related to the risk of NAFLD in lean participants. CONCLUSIONS: A low serum vitamin D level is associated with NAFLD in obese but not lean participants.

Association between Monocyte to High-Density Lipoprotein Cholesterol Ratio and Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study.

BACKGROUND: The aim of the present study was to investigate the association between monocyte to high-density lipoprotein cholesterol ratio (MHR) and nonalcoholic fatty liver disease (NAFLD) in Chinese population. METHODS: We enrolled 14189 individuals who attended their annual health examinations in the study. We performed the anthropometric and laboratory measurements and diagnosed NAFLD by hepatic ultrasonography without evidence of other etiologies of chronic liver disease. Student's t-test, Mann-Whitney U test, and chi-squared (χ 2) test was used to compare the differences of clinical characteristics between participants with or without NAFLD. Pearson's and Spearman's analyses were performed to assess the correlation of MHR and NAFLD risk factors. Univariate and multivariate logistic regression analyses were conducted to explore whether MHR associated with NAFLD. RESULTS: Thirty-five percent of the participants enrolled were diagnosed with NAFLD. Compared with healthy controls, NAFLD patients were male predominant, older, and had higher body mass index, waist circumference, and systolic and diastolic blood pressure, as well as higher levels of alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, triglyceride, total cholesterol, low-density lipoprotein cholesterol, fasting plasma glucose, glycated hemoglobin A1c, and serum uric acid, but lower levels of serum high-density lipoprotein cholesterol. Besides, MHR was significantly higher in NAFLD patients than healthy controls [5.35 (4.18-6.84) versus 4.53 (3.48-5.93), P < 0.001]. MHR quartiles were positively related to the prevalence of NAFLD (P < 0.001 for trend). In multivariate logistic regression analysis, MHR was positively associated with the risk of NAFLD after adjusting age, gender, body mass index, waist circumference, diastolic blood pressure, alanine aminotransferase, triglyceride, total cholesterol, fasting plasma glucose, and serum uric acid (OR: 1.026, 95% CI: 1.002-1.052; P = 0.037). CONCLUSIONS: MHR is significantly and positively associated with the risk of NAFLD.

Association between serum uric acid levels and long-term mortality of metabolic dysfunction-associated fatty liver disease: a nationwide cohort study.

BACKGROUND: The association between hyperuricemia and metabolic dysfunction-associated fatty liver disease (MAFLD) remains undetermined. This study aimed to examine the association of serum uric acid (SUA) levels with prevalence and long-term mortality of MAFLD in a nationally representative sample of US adults. METHODS: This analysis included 11,177 participants from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) with matched mortality data until 2019. We used logistic regression models to estimate the adjusted odd ratios (ORs) for factors associated with risk of MAFLD, and applied restricted cubic spline (RCS) regression to assess the non-linear associations of SUA levels with all-cause and cause-specific mortality of MAFLD. We also used Cox proportional hazards regression analysis to estimate hazard ratios (HRs) for the mortality. RESULTS: A higher SUA level contributed to a significant increased risk of MAFLD. every 1 mg/dL increment of SUA level was related to 17% (95% CI 9-24%) increased risk of MAFLD. Furthermore, a U-shaped association for males and a J-shaped association for females was discovered between SUA levels and all-cause mortality in participants with MAFLD. Specifically, among males, when SUA > 6.7 mg/dL, the higher SUA showed increased risk of cardio-cerebrovascular disease (CVD) mortality [HR (95% CI): 1.29 (1.05-1.58)]. As for females, only when SUA > 5.5 mg/dL, it showed a significantly positive association with risk of CVD and cancer mortality [HR (95% CI) 1.62 (1.24-2.13) and 1.95 (1.41-2.68)]. CONCLUSIONS: Elevated SUA level is significantly associated with an increased risk of MAFLD. Besides, SUA level is also a predictor of long-term mortality of MAFLD.

Olfactomedin 4 deletion exacerbates nonalcoholic fatty liver disease through P62-dependent mitophagy in mice.

BACKGROUND & AIMS: Olfactomedin 4 (OLFM4) is a glycoprotein that is related to obesity and insulin resistance. This study aims to investigate the role and mechanisms of OLFM4 in nonalcoholic fatty liver disease (NAFLD). APPROACH & RESULTS: OLFM4 expression levels were significantly increased in liver samples from NAFLD patients and in cellular and mouse models of NAFLD. Cell lines deficient in or overexpressing OLFM4 and Olfm4-/- mice were established to study its role in NAFLD. OLFM4 deficiency significantly aggravated diet-induced hepatic steatosis and inflammation, while re-expression of OLFM4 ameliorated diet-induced hepatic steatosis and inflammation in mice. Mechanistically, OLFM4 deficiency disrupted mitochondrial structure and decreased mitophagy in hepatocytes, thereby aggravating hepatic lipogenesis, inflammation, and insulin resistance. Moreover, OLFM4 directly interacted with P62, and OLFM4 deficiency decreased mitophagy in both cellular and mouse models of NAFLD through a P62-dependent mechanism. We also show that blocking the P62-ZZ-domain using XRK3F2 prevented diet-induced NAFLD in Olfm4-/- mice. CONCLUSION: OLFM4 is significantly upregulated in NAFLD, and OLFM4 deletion exacerbates NAFLD through P62-dependent mitophagy.

Olfactomedin-4 deletion exacerbates DSS-induced colitis through a matrix metalloproteinase-9-dependent mechanism.

Background and Aims: Olfactomedin-4 is a glycoprotein that is upregulated in inflamed gastrointestinal tissues. This study aimed to investigate the role and underlying mechanisms of olfactomedin-4 in ulcerative colitis. Methods: C57BL/6 mice and olfactomedin-4 knockout mice were fed dextran sulfate sodium in drinking water to establish a colitis model. An in vitro inflammation model was constructed in HCT116 and NCM460 cells stimulated with lipopolysaccharide. The expression of olfactomedin-4 was detected by Western blotting, immunohistochemistry staining, and qRT‒PCR. The differences in the severity of colitis between olfactomedin-4 knockout mice and wild-type mice were compared, and the underlying mechanisms were explored. Results: Olfactomedin-4 expression was significantly upregulated in colonic tissues of active ulcerative colitis patients and in cellular and mouse models of colitis. Compared with wild-type littermates, olfactomedin-4 knockout mice were more susceptible to dextran sulfate sodium-induced colitis and produced higher levels of proinflammatory cytokines and chemokines. In addition, olfactomedin-4 deficiency significantly promoted intestinal epithelial cell apoptosis and increased intestinal permeability, which was mediated by the p53 pathway. Moreover, olfactomedin-4 directly interacted with and negatively regulated matrix metalloproteinase-9. Inhibiting matrix metalloproteinase-9 significantly decreased colonic p53 expression and ameliorated experimental colitis in olfactomedin-4 knockout mice, while overexpression of matrix metalloproteinase-9 aggravated colitis. Further experiments showed that matrix metalloproteinase-9 regulated p53 through the Notch1 signaling pathway to promote ulcerative colitis progression. Conclusions: Olfactomedin-4 is significantly upregulated in ulcerative colitis and may protect against colitis by directly inhibiting matrix metalloproteinase-9 and further decreasing p53-mediated apoptosis via Notch1 signaling.

Functions of amyloid precursor protein in metabolic diseases.

Amyloid precursor protein (APP) is a transmembrane precursor protein that is widely expressed in the central nervous system and peripheral tissues in the liver and pancreas, adipose tissue, and myotubes. APP can be cleaved by proteases in two different ways to produce a variety of short peptides, each with different physiological properties and functions. APP peptides generated by non-amyloidogenic processing can positively influence metabolism, while the peptides produced by amyloidogenic processing have the opposite effects. Here, we summarize the regulatory effects of APP and its cleavage peptides on metabolism in the central nervous system and peripheral tissues. In addition, abnormal expression and function of APP and APP-derived peptides are associated with metabolic diseases, such as type 2 diabetes, obesity, non-alcoholic fatty liver disease, and cardiovascular disease, and cancers. Pharmacological intervention of APP function or reduction of the production of peptides derived from amyloidogenic processing may be effective strategies for the prevention and treatment of Alzheimer's disease, and they may also provide new guidance for the treatment of metabolic diseases.

Association between Serum Uric Acid to HDL-Cholesterol Ratio and Nonalcoholic Fatty Liver Disease in Lean Chinese Adults.

METHODS: A cross-sectional study was performed among 6285 lean Chinese adults (body mass index < 24 kg/m2) who took their annual health checkups. NAFLD was diagnosed based on hepatic ultrasound examination, with exclusion of other etiologies. RESULTS: Of 6285 lean participants enrolled, 654 NAFLD cases were diagnosed. The overall NAFLD prevalence was 10.41%, and the prevalence was 15.45% and 7.16% in men and women, respectively. UHR was significantly higher in NAFLD patients than in controls (14.25 ± 5.33% versus 10.09 ± 4.23%, P < 0.001). UHR quintiles were positively associated with NAFLD prevalence, which was 1.91% in the first UHR quintile and increased to 3.58%, 7.81%, 14.17%, and 24.54% in the second, third, fourth, and fifth quintile groups, respectively (P < 0.001 for trend). Multivariate logistic regression analysis showed that UHR was independently associated with an increased risk of NAFLD (odds ratio: 1.105; 95% CI: 1.076-1.134; P < 0.001). Sensitivity analysis showed that UHR remained significantly associated with NAFLD in lean participants with normal range of serum uric acid and HDL-cholesterol levels. CONCLUSIONS: UHR was significantly associated with NAFLD and may serve as a novel and reliable marker for NAFLD in lean adults.

YY1 promotes colorectal cancer proliferation through the miR-526b-3p/E2F1 axis.

We previously reported that E2F1 expression is up-regulated and positively correlated with the malignant phenotypes of colorectal cancer (CRC). However, the underlying mechanisms leading to the aberrant up-regulation of E2F1 in CRC have not been clarified. In this study, we observed that miR-526b-3p directly targets the 3'UTR of E2f1 mRNA, leading to reduced E2F1 expression. Overexpression of miR-526b-3p inhibited the proliferation of CRC cells by decreasing the level of E2F1. We also found that the Ying Yang 1 (YY1)-dependent transcriptional suppression of miR-526b-3p is responsible for the up-regulation of E2F1 in CRC, in which YY1 binds to the promoter of miR-526b gene and recruits histone deacetylase (HDAC). Knockdown of YY1 led to cell cycle arrest and diminished colony formation in CRC cells partly through relieving the miR-526b-3p suppression. Clinical analysis showed that YY1 and E2F1 were negatively correlated with miR-526b-3p in CRC tissues. Moreover, a high level of YY1 and E2F1, or a low level of miR-526b-3p, predicted poor survival of CRC patients. In conclusion, our findings highlight the dysregulation of the YY1/miR-526b-3p/E2F1 axis in CRC development, implicating a novel regulatory pathway for E2F1 as a potential therapeutic target in CRC.