Maternal Western-Style Diet alters Kupffer Cell proportion leading to Metabolic Dysfunction-Associated Steatotic Liver Disease when challenged with western diet in adulthood

Sarah Jane Miller¹Rachel Janssen²Wanke Zhao²Karen Jonscher^3,4Hua Zhong⁵Christa DeVette⁶Jacob Friedman^2,7*Kurt Zimmerman^5*

• ¹Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States
• ²Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, United States
• ³Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, United States
• ⁴Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences, Oklahoma City, United States
• ⁵Internal Medicine, The University of Oklahoma Health Sciences, Oklahoma City, United States
• ⁶Pediatrics, The University of Oklahoma Health Sciences, Oklahoma City, United States
• ⁷Biochemistry and Physiology, The University of Oklahoma Health Sciences, Oklahoma City, United States

Exposure to maternal western-style diet (mWD) is associated with early development of metabolic dysfunction-associated fatty liver disease (MAFLD) in offspring. Kupffer cells (KCs), the main resident macrophage population in the liver, are known to promote MAFLD progression, however, the effects of mWD on KC subtypes, ontogeny, and gene expression in offspring are not fully understood. In this manuscript, we used two different models of mWD exposure and challenge in adulthood to understand the impact of mWD on KC proportion, ontogeny, and gene expression in adult offspring. Our data indicate that in the absence of challenge in adulthood, mWD results in increased KC proportion in offspring, with limited changes in KC ontogeny or liver phenotype. In contrast, mWD mice challenged with WD in adulthood had increased expression of inflammatory (Nlrp3) and fibrosis (Tgfb1) related genes compared to chow (CH)-WD fed mice. Although KC proportion and ontogeny were similar when comparing CH-WD and WD-WD fed mice, we found that WD-WD mice had a greater reduction in KC proportion and TdT labelling than CH-WD fed mice when normalized to their respective maternal diet controls. Similar results were found when mice were weaned onto normal chow and re-challenged with WD later on in adulthood. Bulk RNA sequencing data indicate that KCs from mWD mice re-challenged with WD in adulthood had increased expression of inflammatory and antigen presenting genes compared to KCs isolated from WD fed mice lacking mWD exposure. These findings highlight the intergenerational repercussions of mWD on liver phenotype as well as KC proportion and ontogeny and provide novel insight into the mechanisms dictating MAFLD.