Gastric bypass resolves metabolic dysfunction-associated fatty liver disease (MAFLD) in low-BMI patients: A prospective cohort study.

OBJECTIVE: Metabolic dysfunction-associated fatty liver disease (MAFLD) reflects the multifactorial pathogenesis of fatty liver disease in metabolically sick patients. The effects of metabolic surgery on MAFLD have not been investigated. This study assesses the impact of Roux-en-Y gastric bypass (RYGB) on MAFLD in a prototypical cohort outside the guidelines for obesity surgery. RESEARCH DESIGN METHODS: Twenty patients were enrolled in this prospective, single-arm trial investigating the effects of RYGB on advanced metabolic disease (DRKS00004605). Inclusion criteria were an insulin-dependent T2D, BMI of 25-35 kg/m2, glucagon-stimulated C-peptide of >1.5 ng/mL, HbA1c >7%, and age 18-70 years. A RYGB with intraoperative liver biopsies and follow-up liver biopsies three years later. Steatohepatitis was assessed by expert liver pathologists. Data were analyzed using the Wilcoxon rank sum test and a p-value <0.05 was defined as significant. RESULTS: MAFLD completely resolved in all patients three years after RYGB while fibrosis improved as well. Fifty-five percent were off insulin therapy with a significant reduction in HbA1c (8.45±0.27% to 7.09±0.26%, P=0.0014). RYGB reduced systemic and hepatic nitrotyrosine levels likely through upregulation of NRF1 and its dependent anti-oxidative and mitochondrial genes. Additionally, central metabolic regulators such as SIRT1 and FOXO1 were upregulated while denovo lipogenesis was reduced and β-oxidation was improved in line with an improvement of insulin resistance. Lastly, gastrointestinal hormones and adipokines secretion were changed favorably. CONCLUSIONS: RYGB is a promising therapy for MAFLD even in low-BMI patients with insulin-treated T2D with complete histologic resolution. RYGB restores the oxidative balance, adipose tissue function, and gastrointestinal hormones

Diet-dependent function of the extracellular matrix proteoglycan Lumican in obesity and glucose homeostasis.

Objective: Extracellular matrix remodeling is required for adipose expansion under increased caloric intake. In turn, inhibited expandability due to aberrant collagen deposition promotes insulin resistance and progression towards the metabolic syndrome. An emerging role for the small leucine-rich proteoglycan Lumican in metabolically driven nonalcoholic fatty liver disease sparks an interest in further understanding its role in diet-induced obesity and metabolic complications.Methods: Whole body ablation of Lumican (Lum(-/-)) gene and adeno-associated virus-mediated over-expression were used in combination with control or high fat diet to assess energy balance, glucose homeostasis as well as adipose tissue health and remodeling.Results: Lumican was found to be particularly enriched in the stromal cells isolated from murine gonadal white adipose tissue. Likewise murine and human visceral fat showed a robust increase in Lumican as compared to fat from the subcutaneous depot. Lumican null female mice exhibited moderately increased fat mass, decreased insulin sensitivity and increased liver triglycerides in a diet-dependent manner. These changes coincided with inflammation in adipose tissue and no overt effects in adipose expandability, i.e. adipocyte formation and hypertrophy. Lumican over-expression in visceral fat and liver resulted in improved insulin sensitivity and glucose clearance.Conclusions: These data indicate that Lumican may represent a functional link between the extracellular matrix, glucose homeostasis, and features of the metabolic syndrome. (C) 2018 The Authors. Published by Elsevier GmbH

Author Correction: Auto-aggressive CXCR6⁺ CD8 T cells cause liver immune pathology in NASH.

In this Article, the surname of Tobias Boettler was incorrectly shown as ‘Böttler’, and the surname of author Jan-Philipp Mallm was incorrectly shown as ‘Malm’. The original Article has been corrected online