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.
Keywords: Cholesterol; Fatty liver; Insulin resistance; Transporter; triglycerides.