Acylated and desacyl ghrelin are associated with hepatic lipogenesis, β-oxidation and autophagy: role in NAFLD amelioration after sleeve gastrectomy in obese rats
Ezquerro S (1,2,3), Méndez-Giménez L (1,2,3), Becerril S (1,2,3), Moncada R (2,3,4), Valentí V (2,3,5), Catalán V (1,2,3), Gómez-Ambrosi J (1,2,3), Frühbeck G (1,2,3,6), Rodríguez A (1,2,3).
(1) Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
(2) CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
(3) Obesity &Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
(4) Department of Anesthesia, Clínica Universidad de Navarra, Pamplona, Spain.
(5) Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain.
(6) Department of Endocrinology &Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
Bariatric surgery improves non-alcoholic fatty liver disease (NAFLD). Our aim was to investigate the potential role of ghrelin isoforms in the resolution of hepatic steatosis after sleeve gastrectomy, a restrictive bariatric surgery procedure, in diet-induced obese rats.
Male Wistar rats (n = 161) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions [fed ad libitum a normal (ND) or a high-fat (HFD) diet or pair-fed].
Obese rats developed hepatosteatosis and showed decreased circulating desacyl ghrelin without changes in acylated ghrelin. Sleeve gastrectomy induced a dramatic decrease of desacyl ghrelin, but increased the acylated/desacyl ghrelin ratio. Moreover, sleeve gastrectomy reduced hepatic triglyceride content and lipogenic enzymes Mogat2 and Dgat1, increased mitochondrial DNA amount and induced AMPK-activated mitochondrial FFA β-oxidation and autophagy to a higher extent than caloric restriction. In primary rat hepatocytes, the incubation with both acylated and desacyl ghrelin (10, 100 and 1,000 pmol/L) significantly increased TG content, triggered AMPK-activated mitochondrial FFA β-oxidation and autophagy.
Our data suggest that the decrease in the most abundant isoform, desacyl ghrelin, after sleeve gastrectomy contributes to the reduction of lipogenesis, whereas the increased relative acylated ghrelin levels activate factors involved in mitochondrial FFA β-oxidation and autophagy in obese rats, thereby ameliorating NAFLD.
CITATION Sci Rep. 2016 Dec 23;6:39942. doi: 10.1038/srep39942