Acylated and desacyl ghrelin are associated with hepatic lipogenesis, β-oxidation and autophagy: role in NAFLD amelioration after sleeve gastrectomy in obese rats

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.

Ghrelin mediated neuroprotection - A possible therapy for Parkinson's disease?

“…For example, CR in acyl-ghrelin deficient (Goat -/-) mice leads to a reduction in LC3-II in liver, suggesting a decreased rate of autophagy (Yuanyuan Zhang, Fang, Goldstein, Brown, & Zhao, 2015). The treatment of hepatic cells with ghrelin leads to an increase in LC3-II, ATG5, ATG7 as well as a decrease in p62 (Sqstm1), consistent with increased rates of autophagy (Ezquerro et al, 2016). Ghrelin increases LC3 and Beclin1 in an AMPK dependent manner in rat smooth muscle cells (Xu, Liu, Song, Chen, & Gui, 2017), and ghrelin-induced autophagy may occur via activation of AMPK to prevent lipotoxicity in human liver cells (Mao et al, 2015).…”

The Homeostatic Force of Ghrelin

“…Ghrelin activates AMPK in hepatocytes, promotes autophagy, stimulates mitochondrial biogenesis, and induces mitochondrial FFA b-oxidation, and thus ameliorates hepatic triglyceride overaccumulation (Ezquerro et al, 2016) (Figure 3A). In concert, ghrelin attenuates hepatic lipotoxicity by enhancing autophagy via restoration of the AMPK/mTOR signaling pathway (Mao et al, 2015a).…”

FK866 attenuates acute hepatic failure through c-jun-N-terminal kinase (JNK)-dependent autophagy

“…Furthermore, there is increasing evidence suggesting that autophagy plays a protective role in acute liver injury caused by a variety of challenges including LPS, cecal ligation and puncture (CLP), TNFα, APAP, ischemia/reperfusion, overload of fatty acids 18, 20–22 . It is possible that FK866 could protect liver injury through induction of autophagy.…”