Background and Aims
Hydrogen sulfide (H2S) plays a protective role in NAFLD. However, whether cystathionine γ lyase (CSE), a dominant H2S generating enzyme in hepatocytes, has a role in the ...pathogenesis of NAFLD is currently unclear.
Approach and Results
We showed that CSE protein expression is dramatically downregulated, especially in fibrotic areas, in livers from patients with NAFLD. In high‐fat diet (HFD)‐induced NAFLD mice or an oleic acid‐induced hepatocyte model, the CSE/H2S pathway is also downregulated. To illustrate a regulatory role for CSE in NAFLD, we generated a hepatocyte‐specific CSE knockout mouse (CSELKO). Feeding an HFD to CSELKO mice, they showed more hepatic lipid deposition with increased activity of the fatty acid de novo synthesis pathway, increased hepatic insulin resistance, and higher hepatic gluconeogenic ability compared to CSELoxp control mice. By contrast, H2S donor treatment attenuated these phenotypes. Furthermore, the protection conferred by H2S was blocked by farnesoid X receptor (FXR) knockdown. Consistently, serum deoxycholic acid and lithocholic acid (FXR antagonists) were increased, and tauro‐β‐muricholic acid (FXR activation elevated) was reduced in CSELKO. CSE/H2S promoted a post‐translation modification (sulfhydration) of FXR at Cys138/141 sites, thereby enhancing its activity to modulate expression of target genes related to lipid and glucose metabolism, inflammation, and fibrosis. Sulfhydration proteomics in patients' livers supported the CSE/H2S modulation noted in the CSELKO mice.
Conclusions
FXR sulfhydration is a post‐translational modification affected by hepatic endogenous CSE/H2S that may promote FXR activity and attenuate NAFLD. Hepatic CSE deficiency promotes development of nonalcoholic steatohepatitis. The interaction between H2S and FXR may be amenable to therapeutic drug treatment in NAFLD.
Hepatocytic endogenous CSE/H2S sulfhydrates FXR at Cys138/141 sites, promotes FXR activity; on the one hand, inhibits fatty acid de novo synthesis related genes transcription, resulting in reduction of NAFLD; the other, modulates lipid and glucose metabolism, fibrosis and inflammation correlated gene’s transcription, attenuating insulin resistance and subsequent liver fibrosis.
The clinical manifestations of NAFLD (both hepatic and extrahepatic) depend on the outcome of complex interactions between its primary drivers including poor lifestyle habits and diet, a ...dysfunctional microbiota, genetic predisposition, and environmental cues that result in metabolic dysfunction and liver disease. Importantly, MAFLD brings the liver disease into closer alignment with our current understanding of obesity, metabolic syndrome, and systems biology. ...for clinicians, the definition simplifies the diagnostic process by using “positive” criteria rather than exclusionary ones and establishes a conceptual framework grounded in science for considering other etiologies that might contribute to fatty liver diseases. In other words, it captures the full spectrum of the disease. ...cryptogenic cirrhosis” and lean MAFLD can now be diagnosed by physiological and metabolic criteria rather than being viewed as completely separate entities.
LINKED CONTENT
This article is linked to Zhan et al papers. To view these articles, visit https://doi.org/10.1111/apt.17635 and https://doi.org/10.1111/apt.17651
The Corona Virus Disease 2019 (COVID‐19) pandemic has attracted increasing worldwide attention. While metabolic‐associated fatty liver disease (MAFLD) affects a quarter of world population, its ...impact on COVID‐19 severity has not been characterized. We identified 55 MAFLD patients with COVID‐19, who were 1:1 matched by age, sex and obesity status to non‐aged severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐infected patients without MAFLD. Our results demonstrate that in patients aged less than 60 years with COVID‐19, MAFLD is associated with an approximately fourfold increase (adjusted odds ratio 4.07, 95% confidence interval 1.20‐13.79, P = .02) in the probability for severe disease, after adjusting for confounders. Healthcare professionals caring for patients with COVID‐19 need to be aware that there is a positive association between MAFLD and severe illness with COVID‐19.
Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in more than 5% of hepatocytes in the absence of excessive alcohol consumption and other secondary causes of ...hepatic steatosis. In 2020, the more inclusive term metabolic (dysfunction)-associated fatty liver disease (MAFLD) - defined by broader diagnostic criteria - was proposed to replace the term NAFLD. The new terminology and revised definition better emphasize the pathogenic role of metabolic dysfunction and uses a set of definitive, inclusive criteria for diagnosis. Diagnosis of MAFLD is based on evidence of hepatic steatosis (as assessed by liver biopsy, imaging techniques or blood biomarkers and scores) in persons who are overweight or obese and have type 2 diabetes mellitus or metabolic dysregulation, regardless of the coexistence of other liver diseases or excessive alcohol consumption. The known association between NAFLD and chronic kidney disease (CKD) and our understanding that CKD can occur as a consequence of metabolic dysfunction suggests that individuals with MAFLD - who by definition have fatty liver and metabolic comorbidities - are at increased risk of CKD. In this Perspective article, we discuss the clinical associations between MAFLD and CKD, the pathophysiological mechanisms by which MAFLD may increase the risk of CKD and the potential drug treatments that may benefit both conditions.
The rising prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD) poses a significant global health challenge, affecting over 30% of adults worldwide. MASLD is linked to ...increased mortality rates and substantial healthcare costs, primarily driven by its progression to metabolic dysfunction‐associated steatohepatitis (MASH), which can lead to severe liver complications including cirrhosis and hepatocellular carcinoma. Despite its growing burden, effective pharmacotherapy for MASLD/MASH has been lacking until the recent conditional approval of resmetirom by the FDA. Resmetirom, a liver‐targeted thyroid hormone receptor‐β selective drug, has shown promise in clinical trials for treating non‐cirrhotic MASH with moderate to advanced fibrosis. It has demonstrated efficacy in reducing hepatic fat content, improving liver histology (both MASH resolution and fibrosis improvement), and ameliorating biomarkers of liver damage without significant effects on body weight or glucose metabolism. Notably, resmetirom also exhibits favourable effects on circulating lipids, potentially reducing cardiovascular risk in MASLD/MASH patients. The safety profile of resmetirom appears acceptable, with gastrointestinal adverse events being the most common, though generally mild or moderate. However, long‐term surveillance is warranted to monitor for potential risks related to thyroid, gonadal, or bone diseases. Clinical implementation of resmetirom faces challenges in patient selection and monitoring treatment response, and will heavily rely on non‐invasive tests for liver fibrosis assessment. Nonetheless, resmetirom represents a landmark breakthrough in MASLD/MASH treatment, paving the way for future therapeutic strategies aiming to mitigate the multifaceted risks associated with this complex metabolic liver disease.
The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has attracted increasing worldwide attention. Cases of liver damage or ...dysfunction (mainly characterized by moderately elevated serum aspartate aminotransferase levels) have been reported among patients with COVID-19. However, it is currently uncertain whether the COVID-19-related liver damage/dysfunction is due mainly to the viral infection per se or other coexisting conditions, such as the use of potentially hepatotoxic drugs and the coexistence of systemic inflammatory response, respiratory distress syndrome-induced hypoxia, and multiple organ dysfunction. Based on the current evidence from case reports and case series, this review article focuses on the demographic and clinical characteristics, potential mechanisms, and treatment options for COVID-19-related liver dysfunction. This review also describes the geographical and demographic distribution of COVID-19-related liver dysfunction, as well as possible underlying mechanisms linking COVID-19 to liver dysfunction, in order to facilitate future drug development, prevention, and control measures for COVID-19.
Inflammation plays an important role in the initiation and progression of acute kidney injury (AKI). However, evidence regarding the prognostic effect of the platelet-to-lymphocyte ratio (PLR), a ...novel systemic inflammation marker, among patients with AKI is scarce. In this study, we investigated the value of the PLR in predicting the outcomes of critically ill patients with AKI.
Patient data were extracted from the Multiparameter Intelligent Monitoring in Intensive Care Database III version 1.3. PLR cutoff values were determined using smooth curve fitting or quintiles and were used to categorize the subjects into groups. The clinical outcomes were 30-day and 90-day mortality in the intensive care unit (ICU). Cox proportional hazards models were used to evaluate the association between the PLR and survival.
A total of 10,859 ICU patients with AKI were enrolled. A total of 2277 thirty-day and 3112 ninety-day deaths occurred. A U-shaped relationship was observed between the PLR and both 90-day and 30-day mortality, with the lowest risk being at values ranging from 90 to 311. The adjusted HR (95% CI) values for 90-day mortality given risk values < 90 and > 311 were 1.25 (1.12-1.39) and 1.19 (1.08-1.31), respectively. Similar trends were observed for 30-day mortality or when quintiles were used to group patients according to the PLR. Statistically significant interactions were found between the PLR and both age and heart rate. Younger patients (aged < 65 years) and those with more rapid heart rates (≥89.4 beats per minute) tended to have poorer prognoses only when the PLR was < 90, whereas older patients (aged ≥ 65 years) and those with slower heart rates (<89.4 beats per minute) had higher risk only when the PLR was > 311 (P < 0.001 for age and P < 0.001 for heart rate).
The preoperative PLR was associated in a U-shaped pattern with survival among patients with AKI. The PLR appears to be a novel, independent prognostic marker of outcomes in critically ill patients with AKI.
PDF
