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Background and Aims: Although qualitative and quantitative alterations in liver Polyunsaturated Fatty Acids (PUFAs) are observed in MASH in humans, a causal relationship of PUFAs biosynthetic pathways is yet to be clarified. ELOVL5, an essential enzyme in PUFA elongation regulates hepatic triglyceride metabolism. Nonetheless, the long-term consequences of elongase disruption, particularly in murine models of MASH, have not been evaluated., Approach & Results: In humans, transcriptomic data indicated that PUFAs biosynthesis enzymes and notably ELOVL5 were induced during MASH progression. Moreover, gene module association determination revealed that ELOVL5 expression was associated with mitochondrial function in both humans and mice. WT and Elovl5-deficient mice were fed a high-fat, high-sucrose (HF/HS) diet for four months. Elovl5 deficiency led to limited systemic metabolic alterations but significant hepatic phenotype was observed in Elovl5-/- mice after the HF/HS diet, including hepatomegaly, pronounced macrovesicular and microvesicular steatosis, hepatocyte ballooning, immune cell infiltration, and fibrosis. Lipid analysis confirmed hepatic triglyceride accumulation and a reshaping of FA profile. Transcriptomic analysis indicated significant upregulation of genes involved in immune cell recruitment and fibrosis, and downregulation of genes involved in oxidative phosphorylation in Elovl5-/- mice. Alterations of FA oxidation and energy metabolism were confirmed by non-targeted metabolomic approach. Analysis of mitochondrial function in Elovl5-/- mice showed morphological alterations, qualitative cardiolipin changes with an enrichment in species containing shorter unsaturated FAs, and decreased activity of I and III respiratory chain complexes., Conclusion: Enhanced susceptibility to diet-induced MASH and fibrosis in Elovl5-/- mice is intricately associated with disruptions in mitochondrial homeostasis, stemming from a profound reshaping of mitochondrial lipids, notably cardiolipins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The disrupted homeostasis of branched-chain amino acids (BCAAs, including leucine, isoleucine, and valine) has been strongly correlated with diabetes with a potential causal role. However, the relationship between BCAAs and diabetic kidney disease (DKD) remains to be established. Here, we show that the elevated BCAAs from BCAAs homeostatic disruption promote DKD progression unexpectedly as an independent risk factor., Methods and Results: Similar to other tissues, the suppressed BCAAs catabolic gene expression and elevated BCAAs abundance were detected in the kidneys of type 2 diabetic mice and individuals with DKD. Genetic and nutritional studies demonstrated that the elevated BCAAs from systemic disruption of BCAAs homeostasis promoted the progression of DKD. Of note, the elevated BCAAs promoted DKD progression without exacerbating diabetes in the animal models of type 2 DKD. Mechanistic studies demonstrated that the elevated BCAAs promoted fibrosis-associated epithelial-mesenchymal transition (EMT) by enhancing the activation of proinflammatory macrophages through mTOR signaling. Furthermore, pharmacological enhancement of systemic BCAAs catabolism using small molecule inhibitor attenuated type 2 DKD. Finally, the elevated BCAAs also promoted DKD progression in type 1 diabetic mice without exacerbating diabetes., Conclusion: BCAA homeostatic disruption serves as an independent risk factor for DKD and restoring BCAA homeostasis pharmacologically or dietarily represents a promising therapeutic strategy to ameliorate the progression of DKD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Recently, the American Heart Association introduced Life's Essential 8 (LE8) as a new cardiovascular health (CVH) metric, and studies have reported associations between LE8 and CVH outcomes. However, there is limited understanding of LE8's impact on the risk of transitions between different stages of CVH. The current study investigated whether adhering to LE8 during a healthy stage could mitigate the progression from hypertension (HT) to cardiovascular diseases (CVDs), and consequent death., Methods: The study included 107,682 participants in the UK Biobank who were initially free of HT and CVDs. CVH were evaluated using LE8 metrics (diet, physical activity, nicotine exposure, sleep duration, body mass index, non-high-density lipoprotein cholesterol, blood glucose, and blood pressure). Multistate models were used to analyse the impacts of LE8 on the progression of CVDs., Results: During a median follow-up of 12.2 years, 5727 participants developed HT, 7243 developed CVDs, and 1183 died afterwards. LE8 was negatively associated with the dynamic disease progression. A per-10 points increase of CVH scores was significantly associated with the reduced risk [Hazard ratios (95 % confidence intervals)] at 0.71 (0.69, 0.72), 0.83 (0.81, 0.85), 0.79 (0.77, 0.82), and 0.91 (0.86, 0.96) in the transition from healthy to HT, CVDs, death, and from CVDs to death, respectively. Mediation analyses indicated that HT significantly mediated LE8-reduced risks of CVDs and mortality., Conclusions: This study offered evidence that LE8 may influence the stages of CVD progression. The findings underscore the significance of adhering to LE8 in health management and CVDs management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)