Roux-en-Y gastric bypass (RYGB) improves, and can sometimes resolve, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) but data based on histological assessment for the efficacy of sleeve gastrectomy (SG) in resolving NAFLD are sparse. Consequently, we aimed to compare the efficacy of RYGB vs. SG on NAFLD 12 months after surgery. In a prospective cohort study, 40 patients with obesity underwent bariatric surgery (16 RYGB and 24 SG). During surgery, a liver biopsy was taken and repeated 12 months later. NAFLD severity was evaluated using the NAFLD Activity Score (NAS) and Kleiner Fibrosis score. RYGB and SG patients were comparable at baseline. Mean (standard deviation, SD) NAS was 3.3 (0.9) in RYGB and 3.1 (1.4) in SG (p = 0.560) with similar degrees of steatosis, inflammation, and ballooning. Two RYGB patients, and six SG patients, had NASH (p = 0.439). Twelve months after surgery, NAS was significantly and comparably (p = 0.241) reduced in both RYGB (−3.00 (95% CI −3.79–−2.21), p < 0.001) and SG (−2.25 (95% CI −2.92–−1.59), p < 0.001) patients. RYGB patients had significantly more reduced (p = 0.007) liver steatosis (−0.91 (95% CI −1.47–−1.2) than SG patients (−0.33 (95% CI −0.54–−0.13) and greater improvement in the plasma lipid profile. Fibrosis declined non-significantly. NASH was resolved in seven of eight patients without a worsening of their fibrosis. RYGB and SG have similar beneficial effects on NAS and NASH without the worsening of fibrosis. RYGB is associated with a more pronounced reduction in liver steatosis.

Impaired mitochondrial oxidative phosphorylation (OXPHOS) in liver tissue has been hypothesised to contribute to the development of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease (NAFLD). It is unknown whether OXPHOS capacities in human visceral (VAT) and subcutaneous adipose tissue (SAT) associate with NAFLD severity and how hepatic OXPHOS responds to improvement in NAFLD. In biopsies sampled from 62 patients with obesity undergoing bariatric surgery and nine control subjects without obesity we demonstrate that OXPHOS is reduced in VAT and SAT while increased in the liver in patients with obesity when compared with control subjects without obesity, but this was independent of NAFLD severity. In repeat liver biopsy sampling in 21 patients with obesity 12 months after bariatric surgery we found increased hepatic OXPHOS capacity and mitochondrial DNA/nuclear DNA content compared with baseline. In this work we show that obesity has an opposing association with mitochondrial respiration in adipose- and liver tissue with no overall association with NAFLD severity, however, bariatric surgery increases hepatic OXPHOS and mitochondrial biogenesis.

Nonalcoholic fatty liver disease (NAFLD) is associated with impaired hepatic actions of glucagon and insulin. Glucagon and amino acids are linked in an endocrine feedback circuit, the liver–alpha cell axis, that may be disrupted by NAFLD. We investigated how NAFLD severity affects glucagon and insulin resistance in individuals with obesity and whether bariatric surgery improves these parameters. Plasma and liver biopsies from 33 individuals with obesity (collectively, OBE) were obtained before and 12 months after bariatric surgery (Roux‐en‐Y gastric bypass [RYGB] or sleeve gastrectomy [SG]). Nine healthy control individuals (collectively, CON) undergoing cholecystectomy were used as a comparison group. The NAFLD activity score (NAS) was used to subdivide study participants into the following groups: OBE‐no steatosis, OBE+steatosis, and nonalcoholic steatohepatitis (NASH) and/or grade 2 fibrosis (Fib) (OBE‐NASH‐Fib). Measurements of amino acids by targeted metabolomics and glucagon were performed. Glucagon, amino acids (P < 0.05), and the glucagon‐alanine index, a validated surrogate marker of glucagon resistance, were increased in OBE by 60%, 56%, and 61%, respectively, when compared with CON but irrespective of NAFLD severity. In contrast, markers of hepatic insulin resistance increased concomitantly with NAS. Hyperglucagonemia resolved in OBE‐no steatosis and OBE+steatosis but not in OBE‐NASH‐Fib (median, 7.0; interquartile range, 5.0‐9.8 pmol/L), regardless of improvement in insulin resistance and NAS. The type of surgery that participants underwent had no effect on metabolic outcomes. Conclusion: Glucagon resistance to amino acid metabolism exists in individuals with NAFLD independent of NAS severity. Patients with NASH showed persistent hyperglucagonemia 12 months after bariatric surgery, indicating that a disrupted liver–alpha cell may remain in NAFLD despite major improvement in liver histology.

Background: Obesity is associated with an increased risk of cardiometabolic morbidity and mortality, which may be attributable to systemic low-grade inflammation. The impact of bariatric surgery-induced weight loss on low-grade inflammation has not yet thoroughly been described. We investigated the effect of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on the plasma levels of cytokines, chemokines, and cytokine receptors prior to surgery (baseline), and then three and 12 months after surgery. Methods: We recruited 68 individuals (41 females, 27 males) with severe obesity (42.84 ± 6.28) who had been referred for bariatric surgery (RYGB: n = 29, SG: n = 39). Blood samples were collected after an overnight fast at baseline (immediately before surgery), 3 and 12 months after surgery. Eleven patients without obesity or cardiometabolic disease served as controls at baseline. Ninety-two plasma proteins were measured using an Olink Target 96 inflammation panel. Results: We used a linear mixed model to test differences in inflammatory markers at baseline, across time points and between groups. At baseline, 36 cytokines were found to be differentially expressed between the bariatric surgery patients and controls. Of these cytokines, 13 had significantly decreased three months after bariatric surgery and 27 had significantly decreased 12 months after surgery, compared with baseline. Two cytokines (CCL25 and CCL28) increased markedly after 12 months. Only one cytokine (CCL25) was significantly different between the procedures performed, where it increased in the RYGB group 12 months after surgery. Conclusion: Individuals with severe obesity have increased expression of plasma inflammatory cytokines compared to controls, but low-grade inflammation improves following bariatric surgery, regardless of whether it is RYGB or SG.

Non-invasive tests for non-alcoholic fatty liver disease (NAFLD) are needed for assessing disease stage, prognosis and treatment efficacy. Extracellular matrix biomarkers, such as PRO-C3, are useful as biomarkers of advanced liver fibrosis. However, non-invasive biomarkers of early-stage NAFLD, characterized by pericellular fibrosis, are lacking. Here, we measured serological biomarkers of type IV and VIII collagens reflecting the remodeling of the pericellular basement membrane to explore the effect of bariatric surgery on pericellular fibrosis in patients with early NAFLD. Seventy patients with severe obesity underwent bariatric surgery. The cohort consisted of 61 % females who had a mean age of 44. Patients had a median NAFLD activity score of 3 and mild-to-moderate fibrosis F0 (3 %), F1 (86 %), and F2 (11 %). Blood samples were taken at baseline, three, six and 12 months after surgery. At 12 months, 40 patients had a follow-up liver biopsy. The biomarkers PRO-C3, PRO-C4, C4M, and PRO-C8 were measured using indirect competitive ELISAs. Twelve months after surgery patients had significantly lower levels of ALT, GGT, HbA1c, fasting glucose, and CRP. The pericellular fibrosis biomarkers, C4M, PRO-C4, and PRO-C8 decreased by 24 %, 18 % and 44 %, respectively (p < 0.0001), while the interstitial matrix fibrosis marker PRO-C3 remained unchanged. Furthermore, baseline C4M was associated with histologically assessed hepatocyte ballooning and lobular inflammation in patients with (p = 0.032) and without (p = 0.032) steatosis, respectively. Biomarkers of pericellular fibrosis decrease in early-stage NAFLD after patients undergo bariatric surgery and potentially reflect an improvement in liver histology.

Background/Objectives: Visceral adipose tissue (VAT) may play a direct role in the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progression to metabolic dysfunction-associated steatohepatitis (MASH). In this study, we employed untargeted proteomics analyses on paired biopsies from VAT and liver tissues of patients with obesity, MASLD, and MASH. Our objective was to investigate tissue-specific protein expression patterns in search of a potential proteomic signature associated with MASH in both VAT and liver tissue. Methods: VAT and liver tissue were collected from 70 subjects with severe obesity (SWOs) and nine control study subjects without obesity (CON). SWOs were stratified on the basis of liver histology into LS− (no liver steatosis), LS+ (liver steatosis), and MASH. Peptides were extracted from frozen tissue and were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Raw files were analyzed with Spectronaut, proteins were searched against the human FASTA Uniprot database, and the significantly expressed proteins in the two tissues were analyzed. The p-values were false discovery rate (FDR) corrected. Results: A total of 59 VAT and 42 liver proteins were significantly differentially expressed between the four groups: LS−, LS+, MASH, and CON. The majority were upregulated, and many were related to lipid metabolism. In VAT, only one protein, the mitochondrial sulfide:quinone oxidoreductase (SQOR), was significantly downregulated in the MASH group only. In liver tissue from patients with MASH, six proteins were significantly altered compared with the three other groups. Correlation analyses between the top 10 positive VAT and liver proteins were dominated by inflammatory and detoxification proteins. Conclusions: The presence of MASH was not reflected in the VAT proteome, and both the VAT and the liver proteome were generally affected more by the presence of obesity than by MASLD severity. Several immunomodulating proteins correlated significantly between VAT and liver tissue and could reflect common pathophysiological characteristics.