Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression.

Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across multiple species. Furthermore, we identified suppressor of IKKε (SIKE) as a conserved and potent negative controller of MAPK activation. Hepatocyte-specific overexpression of Sike prevented NASH progression in diet- and toxin-induced mouse NASH models. Mechanistically, SIKE directly interacted with TGF-ß-activated kinase 1 (TAK1) and TAK1-binding protein 2 (TAB2) to interrupt their binding and subsequent TAK1-MAPK signaling activation. We found that indobufen markedly up-regulated SIKE expression and effectively improved NASH features in mice and macaques. These findings identify SIKE as a MAPK suppressor that prevents NASH progression and provide proof-of-concept evidence for targeting the SIKE-TAK1 axis as a potential NASH therapy.

TRIM56 protects against nonalcoholic fatty liver disease by promoting the degradation of fatty acid synthase.

Nonalcoholic fatty liver disease (NAFLD) encompasses a disease continuum from simple steatosis to nonalcoholic steatohepatitis (NASH). However, there are currently no approved pharmacotherapies for NAFLD, although several drugs are in advanced stages of clinical development. Because of the complex pathophysiology and heterogeneity of NAFLD, the identification of potential therapeutic targets is clinically important. Here, we demonstrated that tripartite motif 56 (TRIM56) protein abundance was markedly downregulated in the livers of individuals with NAFLD and of mice fed a high-fat diet. Hepatocyte-specific ablation of TRIM56 exacerbated the progression of NAFLD, while hepatic TRIM56 overexpression suppressed it. Integrative analyses of interactome and transcriptome profiling revealed a pivotal role of TRIM56 in lipid metabolism and identified the lipogenesis factor fatty acid synthase (FASN) as a direct binding partner of TRIM56. TRIM56 directly interacted with FASN and triggered its K48-linked ubiquitination-dependent degradation. Finally, using artificial intelligence-based virtual screening, we discovered an orally bioavailable small-molecule inhibitor of FASN (named FASstatin) that potentiates TRIM56-mediated FASN ubiquitination. Therapeutic administration of FASstatin improved NAFLD and NASH pathologies in mice with an optimal safety, tolerability, and pharmacokinetics profile. Our findings provide proof of concept that targeting the TRIM56/FASN axis in hepatocytes may offer potential therapeutic avenues to treat NAFLD.

Prevalence and trend of atrial fibrillation and its associated risk factors among the population from nationwide health check-up centers in China, 2012-2017.

Background: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, which poses huge disease burdens in China. A study was conducted to systematically analyze the recent prevalence trend of AF and age-related disparities in AF risk among the nationwide healthy check-up population. Method: We conducted a nationwide cross-sectional study involving 3,049,178 individuals ≥35 years from health check-up centers to explore the prevalence and trend of AF by age, sex, and region from 2012 to 2017. Additionally, we analyzed risk factors associated with AF among the overall population and different age groups via the Boruta algorithm, the LASSO regression, and the Logistic regression. Result: The age-, sex-. and regional-standardized prevalence of AF kept stable between 0.4%-0.45% among national physical examination individuals from 2012 to 2017. However, the prevalence of AF showed an undesirable upward trend in the 35-44-year age group (annual percentage changes (APC): 15.16 [95%CI: 6.42,24.62]). With increasing age, the risk of AF associated with the overweight or obesity gradually exceeds that associated with diabetes and hypertension. In addition to traditional leading risk factors such as age≥65 and coronary heart disease, elevated uric acid and impaired renal function were tightly correlated with AF in the population. Conclusion: The significant rise in the prevalence of AF in the 35-44 age group reminds us that in addition to the elderly (the high-risk group), younger people seem to be in more urgent need of attention. Age-related disparities in AF risk also exist. This updated information may provide references for the national prevention and control of AF.

Lipoprotein(a) distribution and its association with carotid arteriopathy in the Chinese population.

BACKGROUND AND AIMS: The distribution of lipoprotein(a) [Lp(a)] has not been well-studied in a large population in China. The relationship between Lp(a) and carotid atherosclerosis remains undefined. In this study, we aimed to investigate the distribution of Lp(a) levels and to assess their association with carotid arteriopathy in China. METHODS: In this cross-sectional study, 411,634 adults with Lp(a) measurements from 22 health check-up centers were used to investigate Lp(a) distribution in China. Among participants with Lp(a) data, carotid ultrasound was performed routinely at seven health check-up centers covering 75,305 subjects. Carotid intima-media thickness (cIMT) and carotid plaque were used as surrogate biomarkers of carotid arteriopathy. The multivariate logistic regression model was applied to evaluate the association of increased Lp(a) levels with carotid arteriopathy. RESULTS: The distribution of Lp(a) concentrations was right-skewed, with a median concentration of 10.60 mg/dL. The proportions of Lp(a) levels ≥30 mg/dL and ≥50 mg/dL were 16.75% and 7.10%, respectively. The median Lp(a) level was higher in females individuals in northern China, and increased with age. Spearman's analysis revealed weak correlations between the Lp(a) concentration as a continuous variable and other lipid profiles. The multiple logistic regression analysis showed that participants with Lp(a) levels ≥50 mg/dL had an increased risk of cIMT ≥1.0 mm (OR = 1.138, 95% CI, 1.071-1.208) and carotid plaque (OR = 1.296, 95% CI, 1.219-1.377) compared with those with Lp(a) levels <50 mg/dL. CONCLUSIONS: This is the first study of the Lp(a) distribution in a large population in China. Our findings revealed a positive association between elevated Lp(a) levels (≥50 mg/dL) and increased prevalence of carotid atherosclerosis, which implies an increased risk of cardiovascular disease in the future.

Metabolic dysfunction-associated fatty liver disease increased the risk of subclinical carotid atherosclerosis in China.

Background and aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to substitute NAFLD in 2020. This new term highlights the systematic metabolic disturbances that accompany fatty liver. We evaluated the correlations between MAFLD and subclinical carotid atherosclerosis (SCA) based on a nationwide health examination population in China. Methods: We performed a nationwide cross-sectional population and a Beijing retrospective cohort from 2009 to 2017. SCA was defined as elevated carotid intima-media thickness. The multivariable logistic and Cox models were used to analyze the association between MAFLD and SCA. Results: 153,482 participants were included in the cross-sectional study. MAFLD was significantly associated with SCA in fully adjusted models, with an odds ratio of 1.66; 95% confidence interval (CI): 1.62-1.70. This association was consistent in the cohort, with a hazard ratio (HR) of 1.31. The association between baseline MAFLD and incident SCA increased with hepatic steatosis severity. Subgroup analysis showed an interaction between age and MAFLD, with a higher risk in younger groups (HR:1.67, 95% CI: 1.17-2.40). Conclusion: In this large cross-section and cohort study, MAFLD was significantly associated with the presence and development of SCA. Further, the risk was higher among MAFLD individuals with high hepatic steatosis index and young adults.

Association of the components of ambient fine particulate matter (PM2.5) and chronic kidney disease prevalence in China.

Previous research has implicated PM2.5 as a potential environmental risk factor for CKD, but little is known about the associations between its components and CKD. We conducted a nationwide cross-sectional study using the updated air pollution data in the nationwide population (N = 2,938,653). Using generalized additive models, we assessed the association between long-term exposure to PM2.5 and its components (i.e., black carbon [BC], organic matter [OM], nitrate [NO3-], ammonium [NH4+], sulfate [SO42-]), and CKD prevalence. The air pollution data was estimated using high-resolution and high-quality spatiotemporal datasets of ground-level air pollutants in China. Besides, we adopted a novel quantile-based g-computation approach to assess the effect of a mixture of PM2.5 constituents on CKD prevalence. The average concentration of PM2.5 was 78.67 ± 22.5 µg/m3, which far exceeded WHO AQG. In the fully adjusted generalized additive model, at a 10 km × 10 km spatial resolution, the ORs per IQR increase in previous 1-year average PM2.5 exposures was 1.380 (95%CI: 1.345-1.415), for NH4+ was 1.094 (95%CI: 1.062-1.126), for BC was 1.604 (95%CI: 1.563-1.646), for NO3- was 1.094 (95%CI: 1.060-1.130), for SO42- was 1.239 (95%CI: 1.208-1.272), and for the OM was 1.387 (95%CI: 1.354-1.421), respectively. Subgroup analysis showed females, younger, and healthier were more vulnerable to this effect. In the further exploration of the joint effect of PM2.5 compositions (OR 1.234 [95%CI 1.222-1.246]) per quartile increase in all 5 PM2.5 components, we found that PM2.5SO42- contributed the most. These findings provide important evidence for the positive relationship between long-term exposure to PM2.5 and its chemical constituents and CKD prevalence in a Chinese health check-up population, and identified PM2.5SO42- has the highest contribution to this relationship. This study provides clinical and public health guidance for reducing specific air particle exposure for those at risk of CKD.

Long-term exposure to air pollution and increased risk of atrial fibrillation prevalence in China.

BACKGROUND: Atrial fibrillation (AF) is the most common type of treated heart arrhythmia contributing to adverse cardiovascular events. The association between short-term air pollution exposure and AF episodes has been recognized. But the evidence of the association between long-term air pollution exposure and AF was limited, especially in developing countries. METHODS: We performed a nationwide cross-sectional study among 1,374,423 individuals aged ≥35 years from 13 health check-up centers. Using logistic regression models, we assessed the association between long-term exposure to single air pollution and AF prevalence, including particulate matter (PM2.5 and PM10), ozone (O3) and PM2.5 compositions, which were estimated by high-resolution and high-quality spatiotemporal datasets of ground-level air pollutants for China. The quantile g-computation model was used to explore the joint effect of all exposures to air pollution and the contribution of an individual component to the mixture. RESULTS: In single-pollutant models, an increase of 10 µg/m3 in PM2.5 (OR 1.031[95%CI 1.010,1.053]) and PM10 (OR = 1.021 [95%CI 1.009,1.033]) was positively associated with AF prevalence. The stratified analyses revealed that these associations were significantly stronger in females, people <65 years old, and those with hypertension and diabetes. In the further exploration of the joint effect of PM2.5 compositions (OR 1.060 [95%CI 1.022,1.101]) per quintile increase in all five PM2.5 components), we found that PM2.5 sulfate contributed the most. CONCLUSIONS: These findings provide important evidence for the positive relationship between long-term exposure to air pollution and AF prevalence in China and identify sulfate particles of PM2.5 as having the highest contribution to the overall mixture effects among all PM2.5 chemical constituents.

The rising death burden of atrial fibrillation and flutter in low-income regions and younger populations.

Objective: The aim of the study was to depict the global death burden of atrial fibrillation and/or flutter (AFF) between 1990 and 2019 and predict this burden in the next decade. Methods: We retrieved annual death data on cases and rates of AFF between 1990 and 2019 from the Global Burden of Disease (GBD) Study 2019 and projected the trends for 2020-2029 by developing the Bayesian age-period-cohort model. Results: The global number of deaths from AFF increased from 117,038.00 in 1990 to 315,336.80 in 2019. This number is projected to reach 404,593.40 by 2029. The age-standardized mortality rates (ASMRs) of AFF have increased significantly in low- to middle-sociodemographic index (SDI) regions, which will surpass that in high SDI regions and reach above 4.60 per 100,000 by 2029. Globally, women have a higher ASMR than men, which is largely attributed to disproportionately higher mortality in women than men in lower SDI regions. Notably, AFF-related premature mortality continues to worsen worldwide. A pandemic of high systolic blood pressure and high body mass index (BMI) largely contributes to AFF-associated death. In particular, low- to middle-SDI regions and younger populations are increasingly affected by the rapidly growing current and future risk of high BMI. Conclusion: The global death burden of AFF in low-income countries and younger generations have not been sufficiently controlled in the past and will continue growing in the future, which is largely attributed to metabolic risks, particularly for high BMI. There is an urgent need to implement effective measures to control AFF-related mortality.

The increasing incidence and high body mass index-related burden of gallbladder and biliary diseases-A results from global burden of disease study 2019.

Background: Gallbladder and biliary diseases are common gastrointestinal conditions associated with huge socioeconomic costs and are considered risk factors for cardiovascular diseases and digestive system cancers. The prevalence and incidence of gallbladder and biliary diseases have not received enough attention from 1990 to 2019. Several non-communicable diseases were associated with the incidence of gallbladder and biliary diseases. It is necessary to clarify the change in the incidence and disability burden of gallbladder and biliary diseases worldwide. Methods: Data on high body mass index (BMI)-related disease burden and incidence, years of life lost prematurely, and years lived with disability (YLDs) due to gallbladder and biliary diseases were obtained from the Global Burden of Disease 2019. The estimated annual percentage change was calculated to qualify the gallbladder and biliary disease burden change. Results: The global age-standardized incidence rate has increased from 585.35 per 100,000 (95% UI: 506.05-679.86) in 1990 to 634.32 per 100,000 (95% UI: 540.21-742.93) in 2019. And the increase in incidence was positively correlated with rising high BMI-related summary exposure value. The high BMI-related YLDs of gallbladder and biliary diseases have increased worldwide over time. Globally, the 25-49 age group suffered a rapid rise in incidence and high BMI attributable to the YLDs rate of gallbladder and biliary diseases. Conclusion: The global incidence and high BMI-related YLDs of gallbladder and biliary diseases remain prominent to increase over the past 30 years. Notably, the incidence and high BMI-related YLDs among people aged 25-49 years have rapidly increased over time. Therefore, high BMI should be emphasized in strategic priorities for controlling gallbladder and biliary diseases.

Energy substrate metabolism and oxidative stress in metabolic cardiomyopathy.

Metabolic cardiomyopathy is an emerging cause of heart failure in patients with obesity, insulin resistance, and diabetes. It is characterized by impaired myocardial metabolic flexibility, intramyocardial triglyceride accumulation, and lipotoxic damage in association with structural and functional alterations of the heart, unrelated to hypertension, coronary artery disease, and other cardiovascular diseases. Oxidative stress plays an important role in the development and progression of metabolic cardiomyopathy. Mitochondria are the most significant sources of reactive oxygen species (ROS) in cardiomyocytes. Disturbances in myocardial substrate metabolism induce mitochondrial adaptation and dysfunction, manifested as a mismatch between mitochondrial fatty acid oxidation and the electron transport chain (ETC) activity, which facilitates ROS production within the ETC components. In addition, non-ETC sources of mitochondrial ROS, such as ß-oxidation of fatty acids, may also produce a considerable quantity of ROS in metabolic cardiomyopathy. Augmented ROS production in cardiomyocytes can induce a variety of effects, including the programming of myocardial energy substrate metabolism, modulation of metabolic inflammation, redox modification of ion channels and transporters, and cardiomyocyte apoptosis, ultimately leading to the structural and functional alterations of the heart. Based on the above mechanistic views, the present review summarizes the current understanding of the mechanisms underlying metabolic cardiomyopathy, focusing on the role of oxidative stress.

The prevalence of MAFLD and its association with atrial fibrillation in a nationwide health check-up population in China.

Background and aims: The epidemiological characteristics of MAFLD and its relationship with atrial fibrillation (AF) are limited in China. Therefore, we explored the epidemiological characteristics of MAFLD from adults along with the association of MAFLD and 12-ECG diagnosed AF in a nationwide population from health check-up centers. Methods: This observational study used cross-sectional and longitudinal studies with 2,083,984 subjects from 2009 to 2017. Age-, sex-, and regional-standardized prevalence of MAFLD was estimated. Latent class analysis (LCA) was used to identify subclusters of MAFLD. Multivariable logistic regression and mixed-effects Cox regression models were used to analyze the relationship between MAFLD and AF. Results: The prevalence of MAFLD increased from 22.75% to 35.58% during the study period, with higher rates in males and populations with high BMI or resided in northern regions. The MAFLD population was clustered into three classes with different metabolic features by LCA. Notably, a high proportion of MAFLD patients in all clusters had overweight and prediabetes or diabetes. The MAFLD was significantly associated with a higher risk of AF in the cross-sectional study and in the longitudinal study. In addition, the coexistence of prediabetes or diabetes had the largest impact on subsequent AF. Conclusion: Our findings suggested a high prevalence of MAFLD and a high prevalence of other metabolic diseases in the MAFLD population, particularly overweight and glucose dysregulation. Moreover, MAFLD was associated with a significantly higher risk for existing and subsequent subclinical AF in the Chinese population.

Role of hepatic lipid species in the progression of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease due to the global pandemic of metabolic diseases. Dysregulation of hepatic lipid metabolism plays a central role in the initiation and progression of NAFLD. With the advancement of lipidomics, an increasing number of lipid species and underlying mechanisms associating hepatic lipid components have been revealed. Therefore, the focus of this review is to highlight the links between hepatic lipid species and their mechanisms mediating the pathogenesis of NAFLD. We first summarized the interplay between NAFLD and hepatic lipid disturbances. Next, we focused on reviewing the role of saturated fatty acids, cholesterol, oxidized phospholipids, and their respective intermediates in the pathogenesis of NAFLD. The mechanisms by which monounsaturated fatty acids and other pro-resolving mediators exert protective effects are also addressed. Finally, we further discussed the implication of different analysis approaches in lipidomics. Evolving insights into the pathophysiology of NAFLD will provide the opportunity for drug development.

The E3 Ligase TRIM16 Is a Key Suppressor of Pathological Cardiac Hypertrophy.

BACKGROUND: Pathological cardiac hypertrophy is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase TRIM16 (tripartite motif-containing protein 16) has been recognized as a pivotal regulator to control cell survival, immune response, and oxidativestress. However, the role of Trim16 in cardiac hypertrophy is unknown. METHODS: We generated cardiac-specific knockout mice and adeno-associated virus serotype 9-Trim16 mice to evaluate the function of Trim16 in pathological myocardial hypertrophy. The direct effect of TRIM16 on cardiomyocyte enlargement was examined using an adenovirus system. Furthermore, we combined RNA-sequencing and interactome analysis that was followed by multiple molecular biological methodologies to identify the direct target and corresponding molecular events contributing to TRIM16 function. RESULTS: We found an intimate correlation of Trim16 expression with hypertrophy-related heart failure in both human and mouse. Our functional investigations and unbiased transcriptomic analyses clearly demonstrated that Trim16 deficiency markedly exacerbated cardiomyocyte enlargement in vitro and in transverse aortic constriction-induced cardiac hypertrophy mouse model, whereas Trim16 overexpression attenuated cardiac hypertrophy and remodeling. Mechanistically, Prdx1 (peroxiredoxin 1) is an essential target of Trim16 in cardiac hypertrophy. We found that Trim16 interacts with Prdx1 and inhibits its phosphorylation, leading to a robust enhancement of its downstream Nrf2 (nuclear factor-erythroid 2-related factor 2) pathway to block cardiac hypertrophy. Trim16-blocked Prdx1 phosphorylation was largely dependent on a direct interaction between Trim16 and Src and the resultant Src ubiquitinational degradation. Notably, Prdx1 knockdown largely abolished the anti-hypertrophic effects of Trim16 overexpression. CONCLUSIONS: Our findings provide the first evidence supporting Trim16 as a novel suppressor of pathological cardiac hypertrophy and indicate that targeting the Trim16-Prdx1 axis represents a promising therapeutic strategy for hypertrophy-related heart failure.

Distributions and trends of the global burden of COPD attributable to risk factors by SDI, age, and sex from 1990 to 2019: a systematic analysis of GBD 2019 data.

BACKGROUND: Global distributions and trends of the risk-attributable burdens of chronic obstructive pulmonary disease (COPD) have rarely been systematically explored. To guide the formulation of targeted and accurate strategies for the management of COPD, we analyzed COPD burdens attributable to known risk factors. METHODS: Using detailed COPD data from the Global Burden of Disease study 2019, we analyzed disability-adjusted life years (DALYs), years lived with disability (YLDs), years of life lost (YLLs), and deaths attributable to each risk factor from 1990 to 2019. Additionally, we calculated estimated annual percentage changes (EAPCs) during the study period. The population attributable fraction (PAF) and summary exposure value (SEV) of each risk factor are also presented. RESULTS: From 1990 to 2019, the age-standardized DALY and death rates of COPD attributable to smoking and household air pollution, occupational particles, secondhand smoke, and low temperature presented consistently declining trends in almost all socio-demographic index (SDI) regions. However, the decline in YLD was not as dramatic as that of the death rate. In contrast, the COPD burden attributable to ambient particulate matter, ozone, and high temperature exposure showed undesirable increasing trends in the low- and low-middle-SDI regions. In addition, the age-standardized DALY and death rates attributable to each risk factor except household air pollution and low temperature were the highest in the low-middle-SDI region. In 2019, the COPD burden attributable to smoking ambient particulate matter, ozone, occupational particles, low and high temperature was obviously greater in males than in females. Meanwhile, the most important risk factors for female varied across regions (low- and low-middle-SDI regions: household air pollution; middle-SDI region: ambient particles; high-middle- and high-SDI region: smoking). CONCLUSIONS: Increasing trends of COPD burden attributable to ambient particulate matter, ozone, and high temperature exposure in the low-middle- and low-SDI regions call for an urgent need to implement specific and effective measures. Moreover, considering the gender differences in COPD burdens attributable to some risk factors such as ambient particulate matter and ozone with similar SEV, further research on biological differences between sexes in COPD and relevant policy-making of disease prevention are required.

Global death burden and attributable risk factors of peripheral artery disease by age, sex, SDI regions, and countries from 1990 to 2030: Results from the Global Burden of Disease study 2019.

BACKGROUND AND AIMS: Peripheral artery disease (PAD) is a prevalent cardiovascular disease. Understanding current and future disease burden of PAD and its attributable risk factors is critical for developing prevention measures targeting PAD and associated complications. METHODS: We analyzed the death burden of PAD and the trends of six risk factors from 1990 to 2019 using the updated 2019 Global Burden of Disease study database, and projected the next decade death burden using a Bayesian age-period-cohort (BAPC) model. RESULTS: The global age-standardized mortality rate (ASMR) of PAD has a modest downward trend from 1990 to 2019. Regionally, ASMRs in higher-sociodemographic index (SDI) areas remained more remarkable than in lower-SDI areas by 2019, while the rate of increase in death burden in the lower-SDI regions increased rapidly over time. ASMR in males was greater than in females. In the population aged older than 40 years, the sex difference in PAD-associated mortality decreased with age. High fasting plasma glucose (FPG) became the primary risk factor for PAD-related death. The contributions of risk factors to PAD-related death varied by age group. Kidney dysfunction was the primary contributor to PAD-related death in people aged 40-59 years, particularly in women. CONCLUSIONS: The global death burden of PAD has not substantially decreased over the three decades. There are large variations in the trend of PAD mortality and its attributable risk factors by SDI regions, sex, and age group. Targeted and effective strategies are needed for the management of PAD-related mortality in specific subgroups.

High Remnant Cholesterol Level Potentiates the Development of Hypertension.

Background: Emerging evidence suggests an association between remnant cholesterol (RC) and vascular damage and hypertension. However, this association has not been explored in a large-scale population in China, and a temporal relationship between RC and hypertension also needs to be investigated. Methods: We conducted a retrospective cross-sectional study in 2,199,366 individuals and a longitudinal study in 24,252 individuals with repeated measurements of lipid profile and blood pressure in at least a 3-year follow-up. The logistic model was used to explore the association between lipid components and hypertension in the cross-sectional analysis. The Cox model was used to analyze the association between high RC (HRC) at baseline and the subsequent incidence of hypertension or the association between hypertension at baseline and incidence of HRC. The cross-lagged panel model was applied to analyze the temporal relationship between RC and hypertension. Results: RC level as a continuous variable had the highest correlation with hypertension among lipid profiles, including RC, low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, and triglycerides, with an odds ratio of 1.59 (95% confidence interval: 1.58-1.59). In the longitudinal cohort, HRC at baseline was associated with incident hypertension. We further explored the temporal relationship between RC and hypertension using the cross-lagged analysis, and the results showed that RC increase preceded the development of hypertension, rather than vice versa. Conclusions: RC had an unexpected high correlation with the prevalence and incidence of hypertension. Moreover, RC increase might precede the development of hypertension, suggesting the potential role of RC in the development of hypertension.

Projection of global burden and risk factors for aortic aneurysm - timely warning for greater emphasis on managing blood pressure.

RATIONALE: Aortic aneurysm (AA) is a serious condition that largely increases the risk of aortic dissection and sudden death. Exploring the global burden of disease and changes in risk factors for AA is essential for public health policy development. OBJECTIVE: To project the death burden from AA and its attributable risk factors in the following decade based on the epidemiological data over the past 30 years. METHODS AND RESULTS: We analysed the death burden of AA and trends of four risk factors from 1990-2019 using the updated 2019 Global Burden of Disease study database by Joinpoint regression analysis. Furthermore, we project the AA-related death burden for the next decade using the Bayesian age-period-cohort model. This study discovered that the global burden of death attributable to AA began to increase after decreasing for two decades. This upward trend will continue in the subsequent decade (average annual percent change: 0.318%, 95% CI: 0.288 to 0.348). Meanwhile, the disease burdens in all economic regions except high-middle socio-demographic index (SDI) regions will continuously increase in the next decade, with the fastest acceleration in the low-middle SDI region (average annual percent change: 1.183%, 95% CI: 1.166 to 1.200). Notably, high systolic blood pressure will surpass the contribution of smoking to become the most important risk factor for mortality due to AA. CONCLUSION: This study discovered a rebounding trend in the aortic aneurysm-related death burden globally. High systolic blood pressure will be the top risk factor attributed to death from AA. Therefore, it should be considered as the first-degree risk factor in the guidance of AA management and criteria for population-based screening programs.Key messagesThe death burden of aortic aneurysms is beginning to rebound globally, and the trend will continue for the next decade.High systolic blood pressure will replace smoking as the most important risk factor associated with aortic aneurysm death.

A conventional immune regulator mitochondrial antiviral signaling protein blocks hepatic steatosis by maintaining mitochondrial homeostasis.

BACKGROUND AND AIMS: Although the prevalence of NAFLD has risen dramatically to 25% of the adult population worldwide, there are as yet no approved pharmacological interventions for the disease because of uncertainty about the underlying molecular mechanisms. It is known that mitochondrial dysfunction is an important factor in the development of NAFLD. Mitochondrial antiviral signaling protein (MAVS) is a critical signaling adaptor for host defenses against viral infection. However, the role of MAVS in mitochondrial metabolism during NAFLD progression remains largely unknown. APPROACH AND RESULTS: Based on expression analysis, we identified a marked down-regulation of MAVS in hepatocytes during NAFLD progression. By using MAVS global knockout and hepatocyte-specific MAVS knockout mice, we found that MAVS is protective against diet-induced NAFLD. MAVS deficiency induces extensive mitochondrial dysfunction during NAFLD pathogenesis, which was confirmed as impaired mitochondrial respiratory capacity and membrane potential. Metabolomics data also showed the extensive metabolic disorders after MAVS deletion. Mechanistically, MAVS interacts with the N-terminal stretch of voltage-dependent anion channel 2 (VDAC2), which is required for the ability of MAVS to influence mitochondrial function and hepatic steatosis. CONCLUSIONS: In hepatocytes, MAVS plays an important role in protecting against NAFLD by helping to regulate healthy mitochondrial function. These findings provide insights regarding the metabolic importance of conventional immune regulators and support the possibility that targeting MAVS may represent an avenue for treating NAFLD.

Multiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis.

Lipotoxicity is a recognized pathological trigger and accelerator of nonalcoholic steatohepatitis (NASH). However, the molecular basis of lipotoxicity-induced NASH remains elusive. Here, we systematically mapped the changes in hepatic transcriptomic landscapes in response to lipotoxic insults across multiple species. Conserved and robust activation of the arachidonic acid pathway, in particular the arachidonate 12-lipoxygenase (ALOX12) gene, was closely correlated with NASH severity in humans, macaques with spontaneously developed NASH, as well as swine and mouse dietary NASH models. Using gain- and loss-of-function studies, we found that ALOX12 markedly exacerbated NASH in both mice and Bama pig models. ALOX12 was shown to induce NASH by directly targeting acetyl-CoA carboxylase 1 (ACC1) via a lysosomal degradation mechanism. Overall, our findings reveal a key molecular driver of NASH pathogenesis and suggest that ALOX12-ACC1 interaction may be a therapeutic target in NASH.