GASTRIC BYPASS INCREASES CIRCULATING BILE ACIDS AND ACTIVATES HEPATIC FARNESOID X RECEPTOR (FXR), BUT REQUIRES INTACT PEROXISOME PROLIFERATOR ACTIVATOR RECEPTOR ALPHA (PPAR-A) SIGNALING TO REDUCE LIVER FAT CONTENT.
Guilherme d. Mazzini*, Jad Khoraki, Matthew G. Browning, Yahya Alwatari, Jilin Wu, Huiping Zhou, Guilherme M. Campos
Virginia Commonwealth University, Richmond, VA
Background: Gastric bypass (RYGB) activates the bile acid target farnesoid X receptor (FXR), inhibiting lipogenesis, and activating lipolysis in the liver. Importantly, the peroxisome proliferator activator receptor alpha (PPAR-a), a central regulator of hepatic lipid metabolism, is inducible upon FXR activation. We previously reported concurrent upregulation of hepatic FXR and PPAR-a in human patients 1 year after RYGB. We have since developed a preclinical surgery model to interrogate the effects of RYGB on hepatic FXR and PPAR-a in rats with diet-induced obesity and Non-alcoholic Fatty Liver Disease (NAFLD).
Methods: Male Wistar rats were fed either a high-fat diet (HFD, n=24) or standard chow (n=8) for 12 weeks. Only the rats on HFD developed NAFLD, and were submitted to RYGB (n=11), sham operation and pair-fed to RYGB (Pair-fed sham, n=6), or sham operation alone (Obese sham, n=5). The rats on standard chow were submitted to sham operation (Lean sham, n=8). Post-operatively, 5 RYGB rats received the PPAR-a antagonist GW6417 (RYGB+GW6417 group). All rats were sacrificed at 7 weeks. Total bile acids (BA) were measured in plasma; triglyceride content was quantified in liver, FXR and PPAR-a mRNA expression (and their downstream targets SHP and CPT1-a) were measured in liver.
Results: At sacrifice, there were no weight differences among, RYGB, RYGB+GW6417, Pair-fed sham, or Lean sham groups. The obese sham group was significantly heavier. Obese sham had lower BA levels (Figure 1A) and lower hepatic FXR, SHP, and CPT1-a mRNA expression (P<0.05, Figure 1B) than Lean sham. RYGB had BA levels increased compared to Obese sham group (P<0.05) and similar to the Lean sham group, while the Pair-fed group had lower BA levels similar to the Obese sham (Figure 1A). Also, in RYGB rats, FXR and PPAR-a mRNA expression and signaling were elevated and similar to Lean sham levels (Figure 1B). In contrast, FXR remained lower, and PPAR-a was decreased in Pair-fed sham (Figure 1B). The PPAR-a antagonist GW6417 prevented the post-operative induction of PPAR-a and CPT1-a in RYGB but didn’t stop the upregulation of FXR and SHP mRNA expression (Figure 1B). Figure 2 shows liver triglycerides content in all groups. RYGB and Pair-fed sham had significantly lower triglyceride content, relative to obese sham. Interestingly, blocking PPAR-a in RYGB+GW6471 group resulted in higher liver triglycerides content relative to RYGB, although with similar weight loss.
Conclusions: Experimental RYGB in rats with diet-induced obesity and NAFLD increased plasma BA concentrations, and concurrent upregulated hepatic FXR and PPAR-a, as seen in humans. RYGB leads to significantly lower liver triglycerides content, but the PPAR-a antagonist GW6471 could block this effect, suggesting that intact PPAR-a signaling is essential for resolution of NAFLD after RYGB.
Figure 1.
A: Systemic Bile Acid Levels
B: Selected Liver Genes and Targets mRNA Expression
Figure 2. Liver Triglycerides Levels in Study Groups (mg/g)
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