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Background: Excessive alcohol consumption has a multifaceted impact on the body's metabolic pathways and organ systems. The objectives of this study were to characterize global metabolomic changes and identify specific pathways that are altered in individuals with excessive alcohol use. Methods: This exploratory study included 22 healthy controls with no known history of excessive alcohol use and 38 patients identified as using alcohol excessively. A Fibrosis‐4 score was used to determine the risk of underlying alcohol‐associated liver disease among the excessive drinkers. Results: We found significantly altered urinary and serum metabolites among excessive drinkers, affecting various metabolic pathways including the metabolism of lipids, amino acids and peptides, cofactors and vitamins, carbohydrates, and nucleotides. Levels of two steroid hormones—5alpha‐androstan‐3beta,17beta‐diol disulfate and androstenediol (3beta,17beta) disulfate—were significantly higher in both the serum and urine samples of excessive drinkers. These elevated levels may be associated with a higher risk of liver fibrosis in individuals with excessive alcohol use. Conclusion: Alcohol consumption leads to marked alterations in multiple metabolic pathways, highlighting the systemic impact of alcohol on various tissues and organ systems. These findings provide a foundation for future mechanistic studies aimed at elucidating alcohol‐induced changes in these metabolic pathways and their implications. [ABSTRACT FROM AUTHOR]

Forkhead box O1 (FOXO1) regulates muscle growth, but the metabolic role of FOXO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FOXO1 in skeletal muscle, we generated skeletal muscle–specific Foxo1 inducible knockout (mFOXO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFOXO1 iKO mice and assessed the correlation between FOXO1 and mitochondria-related protein in the skeletal muscle of patients with diabetes. Obese mFOXO1 iKO mice exhibited improved mitochondrial respiratory capacity, which was followed by attenuated insulin resistance, enhanced fatty acid oxidation, and improved skeletal muscle exercise capacity. Transcriptional inhibition of FOXO1 in peroxisome proliferator–activated receptor δ (PPARδ) expression was confirmed in skeletal muscle, and deletion of PPARδ abolished the beneficial effects of FOXO1 deficiency. FOXO1 protein levels were higher in the skeletal muscle of patients with diabetes and negatively correlated with PPARδ and electron transport chain protein levels. These findings highlight FOXO1 as a new repressor in PPARδ gene expression in skeletal muscle and suggest that FOXO1 links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ. Article Highlights: Skeletal muscle FOXO1 is upregulated in metabolically unhealthy conditions, such as obesity and aging. We generated skeletal muscle–specific inducible Foxo1 -deficient mice to clarify the metabolic role of FOXO1 in skeletal muscle. FOXO1 deficiency improved mitochondrial dysfunction by increasing peroxisome proliferator–activated receptor δ (PPARδ) transcription, leading to improved insulin resistance and lipid metabolism in the skeletal muscle of obese mice. This study shows that FOXO1 is a new repressor in PPARδ gene expression in skeletal muscle and links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ. [ABSTRACT FROM AUTHOR]

Ca2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca2+-channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mouse model of ALD. Unbiased transcriptomic analysis reveals PDK4 as a prominently inducible MAM kinase in ALD. Analysis of human ALD cohorts further corroborate these findings. Additional mass spectrometry analysis unveils GRP75 as a downstream phosphorylation target of PDK4. Conversely, non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced MCC complex formation and subsequent mitochondrial Ca2+ accumulation and dysfunction. Finally, ectopic induction of MAM formation reverses the protective effect of PDK4 deficiency in alcohol-induced liver injury. Together, our study defines a mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD. Ca2+ overload-induced mitochondrial dysfunction is considered a contributing factor alcohol-associated liver disease pathogenesis. Here the authors report that PDK4 promotes Ca2 + -channelling complex formation at the endoplasmic reticulum-mitochondria contact sites, which contributes to the pathogenesis of alcohol-associated liver disease in studies with male mouse and hepatocyte models. [ABSTRACT FROM AUTHOR]

Good health depends on the maintenance of metabolic flexibility, which in turn is dependent on the maintenance of regulatory flexibility of a large number of regulatory enzymes, but especially the pyruvate dehydrogenase complex (PDC), because of its central role in carbohydrate metabolism. Flexibility in regulation of PDC is dependent on rapid changes in the phosphorylation state of PDC determined by the relative activities of the pyruvate dehydrogenase kinases (PDKs) and the pyruvate dehydrogenase phosphatases. Inactivation of the PDC by overexpression of PDK4 contributes to hyperglycemia, and therefore the serious health problems associated with diabetes. Loss of regulatory flexibility of PDC occurs in other disease states and pathological conditions that have received less attention than diabetes. These include cancers, non‐alcoholic fatty liver disease, cancer‐induced cachexia, diabetes‐induced nephropathy, sepsis and amyotrophic lateral sclerosis. Overexpression of PDK4, and in some situations, the other PDKs, as well as under expression of the pyruvate dehydrogenase phosphatases, leads to inactivation of the PDC, mitochondrial dysfunction and deleterious effects with health consequences. The possible basis for this phenomenon, along with evidence that overexpression of PDK4 results in phosphorylation of "off‐target" proteins and promotes excessive transport of Ca2+ into mitochondria through mitochondria‐associated endoplasmic reticulum membranes are discussed. Recent efforts to find small molecule PDK inhibitors with therapeutic potential are also reviewed. [ABSTRACT FROM AUTHOR]

Mitochondria-associated endoplasmic reticulum membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex-dependent mechanism. Excessive MAM formation may cause mitochondrial Ca2+ overload and mitochondrial dysfunction. However, the exact implication of MAM formation in metabolic syndromes remains debatable. Here, we demonstrate that PDK4 interacts with and stabilizes the IP3R1-GRP75-VDAC1 complex at the MAM interface. Obesity-induced increase in PDK4 activity augments MAM formation and suppresses insulin signaling. Conversely, PDK4 inhibition dampens MAM formation and improves insulin signaling by preventing MAM-induced mitochondrial Ca2+ accumulation, mitochondrial dysfunction, and ER stress. Furthermore, Pdk4-/- mice exhibit reduced MAM formation and are protected against diet-induced skeletal muscle insulin resistance. Finally, forced formation and stabilization of MAMs with synthetic ER-mitochondria linker prevented the beneficial effects of PDK4 deficiency on insulin signaling. Overall, our findings demonstrate a critical mediatory role of PDK4 in the development of skeletal muscle insulin resistance via enhancement of MAM formation. [ABSTRACT FROM AUTHOR]

Low-dose persistent organic pollutants (POPs), especially organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), have emerged as a new risk factor for type 2 diabetes. We evaluated whether chronic exposure to low-dose POPs affects insulin secretory function of β-cells in humans and in vitro cells. Serum concentrations of OCPs and PCBs were measured in 200 adults without diabetes. Mathematical model-based insulin secretion indices were estimated by using a 2-h seven-sample oral glucose tolerance test. Insulin secretion by INS-1E β-cells was measured after 48 h of treatment with three OCPs or one PCB mixture. Static second-phase insulin secretion significantly decreased with increasing serum concentrations of OCPs. Adjusted means were 63.2, 39.3, 44.1, 39.3, 39.7, and 22.3 across six categories of a summary measure of OCPs (Ptrend = 0.02). Dynamic first-phase insulin secretion remarkably decreased with increasing concentrations of OCPs among only insulin-sensitive individuals (Ptrend = 0.02); the insulin levels among individuals with high OCPs were ∼30% of those with low OCPs. Compared with OCPs, PCBs showed weaker associations. The decreased insulin secretion by INS-1E β-cells was observed for even 1 pmol/L OCP. The data from human and in vitro cell experiments suggest that chronic exposure to low-dose POPs, especially OCPs, can induce pancreatic β-cell dysfunction. [ABSTRACT FROM AUTHOR]

Background and Aims: Long noncoding RNAs constitute a significant portion of the human genome. Among these, lncRNA H19, initially identified for its high expression during fetal development followed by a decline in the liver postnatally, re-emerges in various liver diseases. However, its specific role in alcohol-associated liver disease (ALD) remains unclear., Approach and Results: Elevated H19 levels were detected in peripheral blood and livers of patients with alcohol-associated cirrhosis and hepatitis, as well as in livers of ethanol-fed mice. Hepatic overexpression of H19 exacerbated ethanol-induced liver steatosis and injury. Metabolomics analysis revealed decreased methionine levels in H19-overexpressed mouse livers, attributable to H19-mediated inhibition of betaine homocysteine methyltransferase (BHMT), a crucial enzyme in methionine synthesis. H19 regulated BHMT alternative splicing through polypyrimidine tract-binding protein 1 (PTBP1), resulting in a reduced Bhmt protein-coding variant. The maternally specific knockout of H19 (H19Mat+/-) or liver-specific knockout of the H19 differentially methylated domain (H19DMDHep-/-) in ethanol-fed mice upregulated BHMT expression and ameliorated hepatic steatosis. Furthermore, BHMT restoration counteracted H19-induced ethanol-mediated hepatic steatosis., Conclusions: This study identifies a novel mechanism whereby H19, via PTBP1-mediated BHMT regulation, influences methionine metabolism in ALD. Targeting the H19-PTBP1-BHMT pathway may offer new therapeutic avenues for ALD., (Copyright © 2024 American Association for the Study of Liver Diseases.)