Search

Background & Aims: Regression of cirrhosis has been observed in patients with viral and non-viral etiologies of liver disease in whom the underlying cause of liver injury was effectively suppressed. However, the understanding of the factors contributing to reversibility of fibrosis and cirrhosis is limited. Our aims were to assess clinical factors, perform genotyping of known variants, and comprehensive metabolic phenotyping to characterize the regression of fibrosis in patients with compensated advanced chronic liver disease (cACLD)., Methods: In a case-control pilot study of 81 patients with cACLD, we compared individuals exhibiting histological or clinical evidence of cACLD regression ("regressors"; n = 44) with those showing no improvement ("non-regressors"; n = 37) after a minimum of 24 months of successful treatment of the cause of liver disease. Data were validated using an external validation cohort (n = 30)., Results: Regardless of the cause of cACLD, the presence of obesity (odds ratio [OR] 0.267 95% CI 0.072-0.882; p = 0.049), high liver stiffness (OR 0.960, 95% CI 0.925-0.995; p = 0.032), and carriage of GCKR variant rs1260326 (OR 0.148, 95% CI 0.030-0.773; p = 0.019) are associated with a reduced likelihood of fibrosis regression in a subgroup of 60 patients with ACLD genotyped for known genetic variants. Using liver tissue transcriptomics, we identified metabolic pathways differentiating regressors from non-regressors, with top pathways associated with lipid metabolism - especially fatty acids, bile acids, phospholipids, triacylglycerides (biosynthesis), and the carnitine shuttle. In the entire discovery cohort, we further measured metabolites within the defined pathways, which led to the identification of 33 circulating markers differentiating regressors from non-regressors after etiological therapy. The validation cohort confirmed 14 of the differentially expressed markers., Conclusions: We identified and validated a group of lipid biomarkers associated with regression of fibrosis that could be used as non-invasive biomarkers for detecting regression of fibrosis in cACLD., Impact and Implications: Regression of cirrhosis/advanced chronic liver disease (ACLD) after removal of the underlying cause of liver injury has been observed in human cirrhosis. However, detailed characterization of ACLD regression remains an unmet need. In this study, we provide a comprehensive phenotyping of individuals likely to experience ACLD regression. While obesity, carriage of GCKR variant rs1260326 and high liver stiffness were associated with lower likelihood of regression of ACLD, a signature of circulating lipid metabolites enabled differentiation of regressors from non-regressors after effective etiologic therapy. The lipid signature we discovered and externally validated could be used as non-invasive biomarker to detect regression of fibrosis in patients with compensated ACLD., (Copyright © 2024. Published by Elsevier B.V.)

Alteration in lipid metabolism plays a pivotal role in developing metabolic dysfunction-associated steatohepatitis (MASH). However, our understanding of alteration in lipid metabolism across liver zonation in MASH remains limited. Within this study, we investigated MASH-associated zone-specific lipid metabolism in a diet and chemical-induced MASH mouse model. Spatial lipidomics using mass spectrometry imaging in a MASH mouse model revealed 130 lipids from various classes altered across liver zonation and exhibited zone-specific lipid signatures in MASH. Triacylglycerols, diacylglycerols, sphingolipids and ceramides showed distinct zone-specific changes and re-distribution from pericentral to periportal localization in MASH. Saturated and monounsaturated fatty acids (FA) were the primary FA composition of increased lipids in MASH, while polyunsaturated FAs were the major FA composition of decreased lipids. We observed elevated fibrosis in the periportal region, which could be the result of observed metabolic alteration across zonation. Our study provides valuable insights into zone-specific hepatic lipid metabolism and demonstrates the significance of spatial lipidomics in understanding liver lipid metabolism. Identifying unique lipid distribution patterns may offer valuable insights into the pathophysiology of MASH and facilitate the discovery of diagnostic markers associated with liver zonation., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Micronutrient supplementation has been extensively explored as a strategy to improve health and reduce risk of chronic diseases. Fat-soluble vitamins like A and E with their antioxidant properties and mechanistic interactions with lipoproteins, have potentially a key impact on lipid metabolism and lipidemia., Objective: The impact of micronutrients on lipid metabolism requires further investigation including characterization of plasma lipidome following supplementation and any cause-effect on circulating lipids., Design: In this study, we elucidate the effect and associations of a multi-micronutrient intervention in Brazilian children and teens with lipoprotein alterations and lipid metabolism., Results: Our analysis suggests a combination of short and long-term impact of supplementation on lipid metabolism, potentially mediated primarily by α-tocopherol (vitamin E) and retinol (vitamin A). Among the lipid classes, levels of phospholipids, lysophospholipids, and cholesterol esters were impacted the most along with differential incorporation of stearic, palmitic, oleic and arachidonic acids. Integrated analysis with proteomic data suggested potential links to supplementation-mediated alterations in protein levels of phospholipases and pyruvate dehydrogenase kinase 1 (PDK1)., Conclusions: Associations between the observed differences in lipidemia, total triglyceride, and VLDL-cholesterol levels suggest that micronutrients may play a role in reducing these risk factors for cardiovascular disease in children. This would require further investigation., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Recent studies suggest that at least two pools of plasma docosahexaenoic acid (DHA) can supply the brain: non-esterified DHA (NE-DHA) and lysophosphatidylcholine (lysoPtdCho)-DHA. In contrast to NE-DHA, brain uptake of lysoPtdCho-DHA appears to be mediated by a specific transporter, but whether both forms of DHA supply undergo the same metabolic fate, particularly with regards to enrichment of specific phospholipid (PL) subclasses, remains to be determined. This study aimed to evaluate brain uptake of NE-DHA and lysoPtdCho-DHA into brain PL classes. Fifteen-week-old rats were infused intravenously with radiolabelled NE- 14 C-DHA or lysoPtdCho- 14 C-DHA (n=4/group) over five mins to achieve a steady-state plasma level. PLs were extracted from the brain and separated by thin layer chromatography and radioactivity was quantified by liquid scintillation counting. The net rate of entry of lysoPtdCho-DHA into the brain was between 59% and 86% lower than the net rate of entry of NE-DHA, depending on the PL class. The proportion of total PL radioactivity in the lysoPtdCho- 14 C-DHA group compared to the NE- 14 C-DHA group was significantly higher in choline glycerophospholipids (ChoGpl) (48% vs 28%, respectively) but lower in ethanolamine glycerophospholipids (EtnGpl) (32% vs 46%, respectively). In both groups, radioactivity was disproportionally high in phosphatidylinositol and ChoGpl but low in phosphatidylserine and EtnGpl compared to the corresponding DHA pool size. This suggests that DHA undergoes extensive PL remodeling after entry into the brain., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: An aim of weight loss is to reduce the risk of type 2 diabetes (T2D) in obese subjects. However, the relation with long-term glycemic improvement remains unknown., Objective: We evaluated the changes in lipid composition during weight loss and their association with long-term glycemic improvement., Design: We investigated the plasma lipidome of 383 obese, nondiabetic patients within a randomized, controlled dietary intervention in 8 European countries at baseline, after an 8-wk low-caloric diet (LCD) (800-1000 kcal/d), and after 6 mo of weight maintenance., Results: After weight loss, a lipid signature identified 2 groups of patients who were comparable at baseline but who differed in their capacities to lose weight and improve glycemic control. Six months after the LCD, one group had significant glycemic improvement [homeostasis model assessment of insulin resistance (HOMA-IR) mean change: -0.92; 95% CI: -1.17, -0.67)]. The other group showed no improvement in glycemic control (HOMA-IR mean change: -0.26; 95% CI: -0.64, 0.13). These differences were sustained for ≥1 y after the LCD. The same conclusions were obtained with other endpoints (Matsuda index and fasting insulin and glucose concentrations). Significant differences between the 2 groups were shown in leptin gene expression in adipose tissue biopsies. Significant differences were also observed in weight-related endpoints (body mass index, weight, and fat mass). The lipid signature allowed prediction of which subjects would be considered to be insulin resistant after 6 mo of weight maintenance [validation's receiver operating characteristic (ROC) area under the curve (AUC): 71%; 95% CI: 62%, 81%]. This model outperformed a clinical data-only model (validation's ROC AUC: 61%; 95% CI: 50%, 71%; P = 0.01)., Conclusions: In this study, we report a lipid signature of LCD success (for weight and glycemic outcome) in obese, nondiabetic patients. Lipid changes during an 8-wk LCD allowed us to predict insulin-resistant patients after 6 mo of weight maintenance. The determination of the lipid composition during an LCD enables the identification of nonresponders and may help clinicians manage metabolic outcomes with further intervention, thereby improving the long-term outcome and preventing T2D. This trial was registered at clinicaltrials.gov as NCT00390637., (© 2016 American Society for Nutrition.)

In mammals, glycogen synthesis and degradation are dynamic processes regulating blood and cerebral glucose-levels within a well-defined physiological range. Despite the essential role of glycogen in hepatic and cerebral metabolism, its spatiotemporal distribution at the molecular and cellular level is unclear. By correlating electron microscopy and ultra-high resolution ion microprobe (NanoSIMS) imaging of tissue from fasted mice injected with (13)C-labeled glucose, we demonstrate that liver glycogenesis initiates in the hepatocyte perinuclear region before spreading toward the cell membrane. In the mouse brain, we observe that (13)C is inhomogeneously incorporated into astrocytic glycogen at a rate ~25 times slower than in the liver, in agreement with prior bulk studies. This experiment, using temporally resolved, nanometer-scale imaging of glycogen synthesis and degradation, provides greater insight into glucose metabolism in mammalian organs and shows how this technique can be used to explore biochemical pathways in healthy and diseased states., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Brain eicosapentaenoic acid (EPA) levels are 250- to 300-fold lower than docosahexaenoic acid (DHA), at least partly, because EPA is rapidly β-oxidized and lost from brain phospholipids. Therefore, we examined if β-oxidation was necessary for maintaining low EPA levels by inhibiting β-oxidation with methyl palmoxirate (MEP). Furthermore, because other metabolic differences between DHA and EPA may also contribute to their vastly different levels, this study aimed to quantify the incorporation and turnover of DHA and EPA into brain phospholipids. Fifteen-week-old rats were subjected to vehicle or MEP prior to a 5 min intravenous infusion of (14)C-palmitate, (14)C-DHA, or (14)C-EPA. MEP reduced the radioactivity of brain aqueous fractions for (14)C-palmitate-, (14)C-EPA-, and (14)C-DHA-infused rats by 74, 54, and 23%, respectively; while it increased the net rate of incorporation of plasma unesterified palmitate into choline glycerophospholipids and phosphatidylinositol and EPA into ethanolamine glycerophospholipids and phosphatidylserine. MEP also increased the synthesis of n-3 docosapentaenoic acid (n-3 DPA) from EPA. Moreover, the recycling of EPA into brain phospholipids was 154-fold lower than DHA. Therefore, the low levels of EPA in the brain are maintained by multiple redundant pathways including β-oxidation, decreased incorporation from plasma unesterified FA pool, elongation/desaturation to n-3 DPA, and lower recycling within brain phospholipids.