title: Sepsis syndrome stimulates proximal tubule cholesterol synthesis and suppresses the SR-B1 cholesterol transporter.
abstract: BACKGROUND
  Previous studies demonstrate that renal cortical/proximal tubule cholesterol accumulation is part of the renal "stress response." The present study was performed to help define underlying mechanisms, using experimental sepsis as a test model.
  
  
  METHODS
  Male CD-1 mice and female low-density lipoprotein receptor (LDLR) knockout mice were injected with a heat-killed Escherichia coli suspension. Renal cortex and serum were obtained from these and control mice either 4, 6, or 18 hours later. Tissues samples were assayed for free cholesterol (FC), cholesteryl esters (CE), HMG CoA reductase (HMGCR) mRNA, and SR-B1 [the high-density lipoprotein (HDL) receptor/cholesterol transporter]. Statin effects on renal cortical HMGCR mRNA and FC/CE levels also were assessed. Finally, the impact of serum from septic versus normal mice on cultured proximal tubule (HK-2) cell cholesterol levels was assessed.
  
  
  RESULTS
  Sepsis induced approximately 30% and 300 to 500% increases in renal FC and CE content, respectively. Cholesterol accumulation was not blunted in LDLR-/- mice versus their controls. Statin therapy also did not alter sepsis-induced renal FC/CE accumulation. However, statin treatment exerted no discernible intra-renal activity (for example, no rise in renal HMGCR mRNA), despite significant extra-renal activity (25% reduction in serum cholesterol; 400% increase in hepatic HMGCR mRNA). HK-2 cells exposed to septic serum sustained a 40% cholesterol increase, compared to cells exposed to control serum. This response was completely statin inhibited, proving that de novo synthesis was involved. Sepsis markedly suppressed renal levels of SR-B1 (an FC efflux protein). Renal HMGCR mRNA did not fall despite sepsis triggered cholesterol loading, indicating a failure of negative feedback activity.
  
  
  CONCLUSIONS
  Sepsis-induced renal cholesterol accumulation is not simply an intrinsic renal response, since it can be enhanced by circulating "stress factors" that drive HMGCR activity. Sepsis also down-regulates SR-B1. Thus, decreased cell FC efflux, coupled with increased synthesis, may synergistically induce the post-sepsis cholesterol overload state.
authors.affiliation: Department of Medicine, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. dzager@fhcrc.org
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zager
authors.forename: Ali C M
authors.initials: AC
authors.lastname: Johnson
authors.forename: Sherry Y
authors.initials: SY
authors.lastname: Hanson
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D001798:Blood Proteins / Q000494:pharmacology; D018955:CD36 Antigens / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D004926:Escherichia coli; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007672:Kidney Cortex / Q000378:metabolism / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011971:Receptors, Immunologic; D011973:Receptors, LDL / Q000235:genetics; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D018746:Systemic Inflammatory Response Syndrome / Q000378:metabolism* / Q000503:physiopathology*
chemical_list: D001798:Blood Proteins; D018955:CD36 Antigens; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D011758:Pyrroles; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D002784:Cholesterol; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases