Abstract
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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a pathology characterized by intrahepatic triacylglycerol (TG) overaccumulation[1,2], which is commonly associated with obesity, dyslipidemia, insulin resistance and type 2 diabetes[3]
Our findings show that obese rats exhibited lower serum desacyl ghrelin levels without changes in acylated ghrelin and acylated/desacyl ghrelin ratio, which is in agreement with previous reports[20,37,38,39]
Plasma acylated ghrelin remained unchanged after bariatric surgery, which is in accordance with other authors[26,41], and the acylated/desacyl ghrelin ratio increased, suggesting an enhanced post-transcriptional modification in order to maintain the circulating levels of the acylated hormone
Summary
Non-alcoholic fatty liver disease (NAFLD) is a pathology characterized by intrahepatic triacylglycerol (TG) overaccumulation[1,2], which is commonly associated with obesity, dyslipidemia, insulin resistance and type 2 diabetes[3]. Bariatric surgery constitutes an effective treatment for morbid obesity achieving a more sustainable weight loss than that observed with lifestyle changes or pharmacological therapy[9] This procedure significantly improves, or even www.nature.com/scientificreports/. The aim of the present study was to analyze in diet-induced obese rats the implication of ghrelin isoforms in the improvement of hepatosteatosis after sleeve gastrectomy, a restrictive bariatric surgery procedure. In this regard, the potential differences in circulating acylated and desacyl ghrelin concentrations in obesity and after sleeve gastrectomy as well as their association with hepatic lipogenesis, lipophagy and mitochondrial FFA β-oxidation were evaluated. The direct effects of the major isoforms of ghrelin on key regulatory molecules involved in these pathways were studied in primary rat hepatocytes
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