Loss of SVIP Results in Metabolic Reprograming and Increased Retention of Very-Low-Density Lipoproteins in Hepatocytes.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Hepatocytes*/metabolism ; Lipoproteins, VLDL*/metabolism; NF-E2-Related Factor 2/metabolism ; PPAR alpha/metabolism ; Animals ; Rats ; Lipid Metabolism ; Male ; Signal Transduction

Perturbations in the tightly regulated processes of VLDL biosynthesis and secretion can directly impact both liver and cardiovascular health. Patients with metabolic disorders have an increased risk of developing hepatic steatosis, which can lead to cirrhosis. These associated metabolic risks underscore the importance of discerning the role of different cellular proteins involved in VLDL biogenesis, transport, and secretion. Small VCP-Interacting Protein (SVIP) has been identified as a component of VLDL transport vesicles and VLDL secretion. This study evaluates the cellular effects stemming from the CRISPR-Cas9-mediated depletion of SVIP in rat hepatocytes. The SVIP-knockout (KO) cells display an increased VLDL retention with elevated intracellular levels of ApoB100 and neutral lipid staining. RNA sequencing studies reveal an impaired PPARα and Nrf2 signaling in the SVIP KO cells, implying a state of metabolic reprograming, with a shift from fatty acid uptake, synthesis, and oxidation to cells favoring the activation of glucose by impaired glycogen storage and increased glucose release. Additionally, SVIP KO cells exhibit a transcriptional profile indicative of acute phase response (APR) in hepatocytes. Many inflammatory markers and genes associated with APR are upregulated in the SVIP KO hepatocytes. In accordance with an APR-like response, the cells also demonstrate an increase in mRNA expression of genes associated with protein synthesis. Together, our data demonstrate that SVIP is critical in maintaining hepatic lipid homeostasis and metabolic balance by regulating key pathways such as PPARα, Nrf2, and APR.

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1R01DK125596-04 United States NH NIH HHS

Keywords: PPARs; SVIP; VLDL secretion; dyslipidemia; lipids; triglyceride

0 (Lipoproteins, VLDL)
0 (NF-E2-Related Factor 2)
0 (PPAR alpha)

Date Created: 20250814 Date Completed: 20250826 Latest Revision: 20250826

20260130

PMC12347863

10.3390/ijms26157465

40806595