Author information

¹Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, MN 55455, USA.

²Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, 55455, USA.

³Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, 55455, USA.

⁴Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.

⁵Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.

⁶Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA.

⁷Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.

Abstract

For patients with obesity and metabolic syndrome, bariatric procedures such as vertical sleeve gastrectomy (VSG) have a clear benefit in ameliorating metabolic dysfunction-associated steatohepatitis (MASH). While the effects of bariatric surgeries have been mainly attributed to nutrient restriction and malabsorption, whether immuno-modulatory mechanisms are involved remains unclear. Using murine models, we report that VSG ameliorates MASH progression in a weight loss-independent manner. Single-cell RNA sequencing revealed that hepatic lipid-associated macrophages (LAMs) expressing the triggering receptor expressed on myeloid cells 2 (TREM2) repress inflammation and increase their lysosomal activity in response to VSG. Remarkably, TREM2 deficiency in mice ablates the reparative effects of VSG, suggesting that TREM2 is required for MASH resolution. Mechanistically, TREM2 prevents the inflammatory activation of macrophages and is required for their efferocytic function. Overall, our findings indicate that bariatric surgery improves MASH through a reparative process driven by TREM2+ macrophages, providing insights into the mechanisms of disease reversal that may result in new therapies and improved surgical interventions.