RAMP1 signaling attenuates diet-induced steatotic liver disease in mice

<p>Objective: In recent years, most prevalent liver disease is metabolism dysfunction-associated steatotic liver disease (MASLD). MASLD-associated inflammation develops steatohepatitis, which further progresses to liver cirrhosis and liver cancer. Inflammation is regulated by the interaction between the nervous system and the immune system. We reported that a neuropeptide, calcitonin gene-related peptide CGRP acts on the CGRP receptor, receptor activity modulating protein 1 (RAMP1), to suppress inflammation. The objective of the present study examined whether RAMP1 signaling contributed to the progression of liver inflammation in MASLD. </p><p>Methods and Results: Male RAMP1 deficient (RAMP1^–/–) or wild-type (WT) mice were fed a normal diet (ND) or HFD for 12 weeks. HFD-fed RAMP1^–/– mice showed heavier body weights than HFD-fed WT mice, which was associated with high levels of liver weights, ALT, total cholesterol, and glucose. HFD-fed RAMP1^–/– mice had higher gene expression levels related to fibrosis including alpha SMA and collagen 1a1 and to inflammation including TNF and IL-1beta than HFD-fed WT mice. Flow cytometry analysis revealed that both genotypes fed with HFD decreased Kupffer cells (KCs). HFD-fed WT mice showed increased monocyte-derived KCs and monocyte-derived macrophages, while HFD-fed RAMP1^–/– mice showed no changes in monocyte-derived KCs and macrophages.  </p><p>Conclusions:  These results suggested RAMP1 signaling deficiency enhanced diet-induced liver steatosis with liver inflammation and fibrosis.</p>