High Free Cholesterol Bioavailability Drives the Tissue Pathologies in Scarb1 ^−/− Mice

Abstract

Objective: Overall and atherosclerosis-associated mortality is elevated in humans with very high HDL (high-density lipoprotein) cholesterol concentrations. Mice with a deficiency of the HDL receptor, Scarb1 (scavenger receptor class B type 1), are a robust model of this phenotype and exhibit several additional pathologies. We hypothesized that the previously reported high plasma concentration of free cholesterol (FC)–rich HDL in Scarb1 −/ − mice produces a state of high HDL-FC bioavailability that increases whole-body FC and dysfunction in multiple tissue sites. Approach and Results: The higher mol% FC in Scarb1 −/− versus WT (wild type) HDL (41.1 versus 16.0 mol%) affords greater FC bioavailability for transfer to multiple sites. Plasma clearance of autologous HDL-FC mass was faster in WT versus Scarb1 −/− mice. FC influx from Scarb1 −/− HDL to LDL (low-density lipoprotein) and J774 macrophages was greater (≈4×) than that from WT HDL, whereas FC efflux capacity was similar. The higher mol% FC of ovaries, erythrocytes, heart, and macrophages of Scarb1 −/− versus WT mice is associated with previously reported female infertility, impaired cell maturation, cardiac dysfunction, and atherosclerosis. The FC contents of other tissues were similar in the two genotypes, and these tissues were not associated with any overt pathology. In addition to the differences between WT versus Scarb1 −/− mice, there were many sex-dependent differences in tissue-lipid composition and plasma FC clearance rates. Conclusions: Higher HDL-FC bioavailability among Scarb1 −/− versus WT mice drives increased FC content of multiple cell sites and is a potential biomarker that is mechanistically linked to multiple pathologies.

Serum opacity factor rescues fertility among female Scarb1−/− mice by reducing HDL-free cholesterol bioavailability

“…Protein was determined by the DC Protein Assay (Bio-Rad, Inc.). The plasma, HDL, and ovary lipid analyses for WT and Scarb1 −/− have been previously reported ( 17 ) and are included here in Figs. 5 and 6 for comparison to the data for the AAV SOF –treated mice.…”

“…Mice deficient in the HDL receptor, encoded by Scarb1, are a model of female infertility linked to dysfunctional HDL. Plasma HDL-FC concentrations among Scarb1 −/− mice are ∼7–10 times that of WT mice ( 15 ), which increases HDL-FC bioavailability (HDL-FCBI) expressed as the product of HDL particle number (HDL-P) and HDL-mol% FC (100 × moles FC /[moles FC + moles PL ]) ( 16 , 17 ). Thus, HDL-FCBI = HDL-P x HDL-mol% FC.…”

Macrophage SR-B1 in atherosclerotic cardiovascular disease

“…In addition to the pivotal role of SR-B1 in the cellular import of HDL-C, a recent study proposed that large HDL particles enriched in free cholesterol resulting from SR-B1 deficiency may mediate free cholesterol delivery into tissues. This mechanism may equally contribute to their dysfunction in the absence of SR-B1 [38 ▪ ]. Indeed, such elevation of free cholesterol content in ovaries, erythrocytes, heart, lung, and macrophages in Srb1 knockout mice might also contribute to female infertility, impaired red blood cell maturation, cardiac dysfunction, and atherosclerosis development in these mice.…”

“…In double Abca1/Srb1 knockout mice, massive macrophage lipid-loading occurs even under hypocholesterolaemia in these animals [47]. Interestingly, Liu et al [38 ▪ ] recently reported that free cholesterol rich HDL particles generated in SR-B1 deficient mice also favour free cholesterol accumulation in macrophages.…”

Implications of High-Density Cholesterol Metabolism for Oocyte Biology and Female Fertility

“…One of the best described mouse models linking disruptions in HDL metabolism and infertility is the SR-B1 knock out (SR-B1 KO) mouse, generated in M. Krieger´s laboratory 25 years ago to understand the relationship between reverse cholesterol transport and atherosclerosis risk ( Rigotti et al, 1997 ). SR-B1 KO mice display distinctively large HDL enriched in apolipoprotein E (ApoE) and UC and an increased incidence of pathologies in critical physiological systems, including high atherosclerosis susceptibility ( Rigotti et al, 1997 ; Rigotti et al, 2003 ; Hoekstra et al, 2010 ; Liu et al, 2021 ). Unexpectedly, during the generation of SR-B1 KO mice females were found to be sterile ( Trigatti et al, 1999 ).…”