Plasma metabolic alterations in patients with severe obesity and non‐alcoholic steatohepatitis

Abstract

SummaryBackgroundObesity can influence hepatic mitochondrial function, and cause non‐alcoholic steatohepatitis (NASH). Diagnosis and follow‐up rely on invasive liver biopsy so blood‐based markers are urgently required.AimTo investigate whether values of circulating metabolites from energy and one‐carbon (1‐C) metabolism may: (a) reflect hepatic mitochondrial flexibility failure and (b) act as NASH biomarkers.MethodsPatients with severe obesity undergoing bariatric surgery (n = 270) were investigated using quantitative targeted plasma metabolomics. Comparisons were with non‐obese controls without liver disease (n = 50). Obese patients with NASH (n = 53) and without NASH (n = 130) representing extreme groups of liver disease were assessed to test the diagnostic ability of the measured circulating metabolites. Paired liver biopsy and plasma samples from NASH patients were available 1 year post‐surgery and were evaluated to monitor metabolomic changes with liver damage resolution.ResultsWe identified correlations between human liver metabolism and obesity. High‐plasma α‐ketoglutarate (α‐KG) and lactate concentrations in NASH patients indicating citric acid cycle replenishment via glutaminolysis might also be a crucial point in NASH onset. Plasma measurements of α‐KG, β‐hydroxybutyrate, pyruvate and oxaloacetate reduced the uncertainty in clinical diagnosis of NASH [area under receiver operating characteristic curve (AUC) of 0.826] and predicted NASH resolution without ambiguity (AUC of 0.999).ConclusionChanges in plasma mitochondrial metabolites appear to be associated with NASH. These metabolic responses may be dynamically remodelled following resolution of liver damage through massive weight loss.

WITHDRAWN: Glutaminolysis-induced mTORC1 activation drives non-alcoholic steatohepatitis progression

“…22,23 We have recently reported in humans that mitochondrial stress signals, adaptive inflammatory responses and modulation of ROS generation may act as potential initiators of liver disease and consequently therapeutic targets. 3,6 It is difficult to extrapolate conclusions to the general population but the reversibility of NASH in patients with severe obesity undergoing surgery may represent a model to explore this topic.…”

“…This post hoc study includes new objectives derived from a previous prospective longitudinal study searching for plasma biomarkers of obesityassociated liver disease. 6 Among the patients undergoing bariatric surgery who donated intraoperative liver samples, we recruited participants on the opposite sides of the spectrum, namely patients with and without NASH (n = 31, each), who were matched for sex, age, body mass index (BMI) and incidence of metabolic comorbidities. As per protocol, metformin was discontinued before surgery.…”

“…4 Metabolomic studies of NASH remission might offer a unique opportunity to examine the signaling processes that govern the alterations in the liver architecture, the self-perpetuating cycle of oxidative and inflammatory stresses, and the hepatocellular death that characterize NASH. 5,6 We used quantitative targeted metabolomics 7 for the measurement of the concentrations of metabolites from energy and one-carbon (1-C) metabolism pathways in the liver by defining a set of metabolites that could facilitate the assessment of the interconnected pathways that are crucial for mitochondrial processes and the regulation of metabolic reprogramming. 8 These metabolites are also signaling molecules that affect gene expression and chromatin structure and play a direct role in methylation reactions 9 that might explain the emerging relationship between metabolism, methylation, and hepatic steatosis.…”

On the Role of Paraoxonase-1, Chemokine (C-C motif) Ligand 2 and Metabolism in Oxidation, Inflammation and Disease. A 2021 Update

“…Also, we observed pre-surgery differences in plasma and liver markers of oxidative stress and inflammation (including CCL2 and PON1), that were corrected one-year post-surgery [56]. In addition, patients with steatohepatitis presented pre-surgery alterations in energy metabolism, especially in plasma concentrations of α-ketoglutarate and oxaloacetate, which reverted one year post-surgery [57]. Overall, these results suggest an entanglement of PON1 and CCL2 in the regulation of metabolism and mitochondrial function in the liver of experimental animals, and in humans (Figure 1).…”

“…Bariatric surgery is a common treatment in patients with morbid obesity, and offers a unique opportunity to investigate the metabolic derangements associated with NAFLD, especially when comparing the data obtained from a peri-surgical liver biopsy with those obtained from a percutaneous biopsy obtained post-surgery [123]. Recent results from our research group [124][125][126][127] showed that, one year post-bariatric surgery (laparoscopic sleeve gastrectomy), the prevalence of diabetes, hypertension and NAFLD significantly decreased in patients with pre-surgery morbid obesity; the improvements in hepatic histology and function were greater in patients with NASH. We found significant pre-surgery differences in liver markers of oxidative stress and inflammation (including CCL2 and PON1) between patients with, and those without, NASH; which suggested a regulatory role of mitogen-activated protein kinases.…”