Genta Kakiyama, Kei Minowa, Nanah Bai-Kamara, Taishi Hashiguchi, William M. Pandak, Daniel Rodriguez-Agudo
{"title":"StarD5 levels of expression correlate with onset and progression of steatosis and liver fibrosis","authors":"Genta Kakiyama, Kei Minowa, Nanah Bai-Kamara, Taishi Hashiguchi, William M. Pandak, Daniel Rodriguez-Agudo","doi":"10.1152/ajpgi.00024.2024","DOIUrl":null,"url":null,"abstract":"Background and aims: Insufficient expression of steroidogenic acute regulatory lipid transfer protein 5 (StarD5) on liver cholesterol/lipid homeostasis is not clearly defined. Methods: The ablation of StarD5 was analyzed in mice on a normal or western diet (WD) to determine its importance in hepatic lipid accumulation and fibrosis compared to wild type (WT) mice. Rescue experiments in StarD5<sup>-/-</sup> mice and hepatocytes were performed. Results: In addition to increased hepatic triglyceride/cholesterol levels, global StarD5<sup>-/-</sup> mice fed a normal diet displayed reduced plasma triglycerides and liver VLDL secretion as compared with WT counterparts. Insulin levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) scoring were elevated, demonstrating developing insulin resistance (IR). WD fed StarD5<sup>-/-</sup> mice up-regulated TAZ expression with accelerated liver fibrosis when compared to WD-fed WT mice. CYP7B1's suppression coupled with chronic accumulation of toxic oxysterol levels correlated with presentation of fibrosis. 'Hepatocyte selective' StarD5 overexpression in StarD5<sup>-/- </sup>mice restored expression, reduced hepatic triglycerides, and improved HOMA-IR. Observations in 2 additional mouse and one human NASH model were supportive. Conclusions: StarD5's downregulation with hepatic lipid excess is a previously unappreciated physiologic function appearing to promote lipid storage for future needs. Conversely, StarD5's lingering downregulation with prolonged lipid/cholesterol excess accelerates fatty liver's transition to fibrosis; mediated via dysregulation in the oxysterol signaling pathway.","PeriodicalId":7598,"journal":{"name":"American Journal of Physiology - Gastrointestinal and Liver Physiology","volume":"49 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Physiology - Gastrointestinal and Liver Physiology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1152/ajpgi.00024.2024","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Background and aims: Insufficient expression of steroidogenic acute regulatory lipid transfer protein 5 (StarD5) on liver cholesterol/lipid homeostasis is not clearly defined. Methods: The ablation of StarD5 was analyzed in mice on a normal or western diet (WD) to determine its importance in hepatic lipid accumulation and fibrosis compared to wild type (WT) mice. Rescue experiments in StarD5-/- mice and hepatocytes were performed. Results: In addition to increased hepatic triglyceride/cholesterol levels, global StarD5-/- mice fed a normal diet displayed reduced plasma triglycerides and liver VLDL secretion as compared with WT counterparts. Insulin levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) scoring were elevated, demonstrating developing insulin resistance (IR). WD fed StarD5-/- mice up-regulated TAZ expression with accelerated liver fibrosis when compared to WD-fed WT mice. CYP7B1's suppression coupled with chronic accumulation of toxic oxysterol levels correlated with presentation of fibrosis. 'Hepatocyte selective' StarD5 overexpression in StarD5-/- mice restored expression, reduced hepatic triglycerides, and improved HOMA-IR. Observations in 2 additional mouse and one human NASH model were supportive. Conclusions: StarD5's downregulation with hepatic lipid excess is a previously unappreciated physiologic function appearing to promote lipid storage for future needs. Conversely, StarD5's lingering downregulation with prolonged lipid/cholesterol excess accelerates fatty liver's transition to fibrosis; mediated via dysregulation in the oxysterol signaling pathway.