The bile acid activated receptors GPBAR1 and FXR exert antagonistic effects on autophagy

Abstract

Autophagy is a highly conserved catabolic process activated by fasting and caloric restriction. FXR, a receptor for primary bile acids, reverses the activity of cAMP‐response element binding protein (CREB) on autophagy‐related genes (Atg)s and terminates autophagy in the fed state. GPBAR1, a receptor for secondary bile acids, exerts its genomic effects via cAMP‐CREB pathway. By genetic and pharmacological approaches, we have obtained evidence that GPBAR1 functions as a positive modulator of autophagy in liver and white adipose tissue (WAT) in fasting. Mechanistically, we found that Gpbar1−/− mice lack the expression of Cyp2c70 a gene essential for generation of muricholic acids which are FXR antagonists, and have an FXR‐biased bile acid pool. Because FXR represses autophagy, Gpbar1−/− mice show a defective regulation of autophagy in fasting. BAR501, a selective GPBAR1 agonist, induces autophagy in fed mice. Defective regulation of autophagy in Gpbar1−/− could be reversed by FXR antagonism, while repression of autophagy by feeding was partially abrogated by FXR gene ablation, and FXR activation repressed Atgs in the fast state. BAR501 reversed the negative regulatory effects of feeding and FXR agonism on autophagy and promoted the recruitment of CREB to a CRE on the LC3 promoter. In mice exposed to chronic high caloric intake, GPBAR1 agonism ameliorated insulin sensitivity and induced Atgs expression in the liver and WAT. In summary, GPBAR1 is required for positive regulation of autophagy in fasting and its ligands reverse the repressive effects exerted on liver and WAT autophagy flow by FXR in fed.

Reciprocal interactions between gut microbiota and autophagy

“…Bile acids are signaling molecules that can activate nuclear hormone receptors including FXR and TGR5 (also known as GPBAR1), which is a cell-surface receptor of the G protein-coupled receptor family[ 73 ]. These two bile acid receptors have been described to modulate autophagy in the liver and adipose tissue in fed and fasted states[ 74 ].…”

“…Several alterations of autophagy, including a decreased amount of LC3 mRNA and LC3-II and an increased amount of p62, have been observed in the liver of mice fed a high-fat diet (HFD), a potent inducer of dysbiosis[ 74 ]. Chronic exposure of rats to an HFD can lead to NASH (non-alcoholic fatty steatohepatitis).…”

“…Interestingly, supplementation of an HFD with a probiotic strain ( Limosilactobacillus reuteri ) and/or treatment of NASH mice with antibiotics (metronidazole) tended to normalize the hepatic content of these two autophagy-related proteins, as well as SCFAs and Firmicutes and Bacteroidetes fecal contents, thus suggesting a role of the gut microbiota in the modulation of hepatic autophagy[ 75 , 76 ]. To note, some data suggest a role for TGR5 in the regulation of autophagy in response to HFD[ 74 ].…”

Atorvastatin protects against liver and vascular damage in a model of diet induced steatohepatitis by resetting FXR and GPBAR1 signaling

“…Alternatively, atherosclerotic lesions can be promoted by feeding a high fat diet in combination with CA that is the main FXR agonist in mice, highlighting the central role of FXR‐mediated inhibition of CYP7A1 in preventing cholesterol disposal in mice 32 . Consistent with the detrimental role of FXR in regulating cholesterol disposal in mice, MCAs that remove inhibition of FXR on CYP7A1 have been identified as one of the effectors that confers resistance against hypercholesterolemia in rodents feed a cholesterol‐reach diet 16,33,34 …”

“…32 Consistent with the detrimental role of FXR in regulating cholesterol disposal in mice, MCAs that remove inhibition of FXR on CYP7A1 have been identified as one of the effectors that confers resistance against hypercholesterolemia in rodents feed a cholesterol-reach diet. 16,33,34 Building on this background, we have investigated whether modulation of cholesterol biosynthesis by atorvastatin impacts on bile acid homeostasis in a mice model of NAFLD and we have compared the effect of atorvastatin to obeticholic acid, a potent FXR ligand advanced into phase 3 clinical trials in NAFLD/NASH. Our results have also shown that atorvastatin resets bile acid signaling and promotes formation of bile acid species that are GPBAR1 agonists.…”