Ketone-body receptor GPR109A suppresses hepatic inflammation via gut-liver axis regulation

The ketogenic diet (KD) promotes ketone body synthesis and has been used therapeutically for over a century. The therapeutic efficacy of the KD is largely attributed to ketone bodies, {beta}-hydroxybutyrate ({beta}HB), and acetoacetate. GPR109A, the receptor for {beta}HB, has been shown to regulate immune responses, but its role in metabolism remains unclear. This study investigated the role of GPR109A in lipid metabolism under specific ketogenic conditions, such as fasting and KD feeding. Gpr109a-/- mice exhibited increased hepatic lipid accumulation, inflammation, and fibrosis after being fed the KD, indicating that GPR109A, highly expressed in macrophages, modulates macrophage-driven inflammation and thus has a protective role in the liver. In contrast, GPR109A did not contribute to hepatic protection during short-term fasting, suggesting that its role is more pronounced under specific ketogenic conditions. Further analysis of this mechanism revealed that GPR109A protects the liver from inflammation by maintaining intestinal barrier integrity and limiting lipopolysaccharide (LPS) leakage from the gut under diet-induced ketogenic conditions. These findings highlight the novel protective mechanism of GPR109A, via the gut-liver axis, to sustain metabolic homeostasis during the KD. This study provides valuable insights into the physiological effects of ketone bodies.