Stop the Inflammation! The Role of Bile Acid Receptor Agonists in Attenuating the Progression of NAFLD

By: Ramzy Burns

Paper: Bile Acid Receptor Activation Modulates Hepatic Monocyte Activity and Improves Nonalcoholic Fatty Liver Disease http://www.jbc.org/content/288/17/11761.long

Stop the Inflammation! The Role of Bile Acid Receptor Agonists in Attenuating the Progression of NAFLD

In the industrialized world, non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of liver disease and often precedes cirrhosis and liver failure. NAFLD encompasses a spectrum of phenotypic severity, beginning with fat accumulation in the liver (steatosis) and ending in nonalcoholic steatohepatitis which is associated with cirrhosis in 15% of patients. A firm understanding of the mechanisms underlying the progression of NAFLD are critical for combatting the disease. The current knowledge surrounding NAFLD progression suggests a two-hit hypothesis. The first hit is caused by an accumulation of fat in hepatocytes and the second-hit is believed to be caused by inflammation and ROS damage in the liver. Bile acid receptors have been hypothesized to be potential mediators of liver inflammation by signaling through two pathways: farnesoid X receptor, a nuclear hormone receptor, and TGR5, a G-protein coupled receptor. Previous research displayed that FXR-null mice suffered from enhanced necroinflammation and hepatic steatosis. Additionally, agonist-stimulated TGR5 inhibited cytokine release by TLR-activated macrophages thereby reducing inflammation. The effect of a FXR/TGR5 agonist on the progression of NAFLD was previously unknown, but McMahan et al. provide evidence that INT-767, a dual FXR/TGR5 bile acid receptor agonist, is capable of attenuating inflammation in a mouse model of obesity.

By administering INT-767 to an obesity mouse model and assessing the liver through trichome staining, the authors establish that bile acid receptor agonist (INT-767) decreased liver inflammation. qPCR revealed that INT-767 administration reduced the expression of IL-18 and TNFα, suggesting that the proinflammatory cytokine profile is altered in response to INT-767. Using flow cytometric analysis, the researchers found that there was increased infiltration of Ly6Clow and decreased levels of Ly6Chigh monocytes in INT-767 treated mouse livers, indicating a switch to an anti-inflammatory state caused by decreased expression of Ly6Con monocytes in the liver. Lastly, qPCR displayed that genes associated with alternatively activated macrophages, which promote an anti-inflammatory state, were upregulated when treated with INT-767, confirming the change from proinflammatory macrophages to anti-inflammatory macrophages. The role of the INT-767-activated bile acid receptor in promoting an anti-inflammatory state in the liver displays a novel role for bile acid receptor agonists in attenuating liver inflammation and halting the progression of NAFLD. Creating a clinically relevant bile acid receptor agonist could be beneficial in stopping the progression of NAFLD to its most severe forms.

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