DHCR7 Expression Predicts Poor Outcomes and Mortality From Sepsis

Abstract

IMPORTANCE: This is a study of lipid metabolic gene expression patterns to discover precision medicine for sepsis.OBJECTIVES: Sepsis patients experience poor outcomes including chronic critical illness (CCI) or early death (within 14 d). We investigated lipid metabolic gene expression differences by outcome to discover therapeutic targets. DESIGN, SETTING, AND PARTICITPANTS:Secondary analysis of samples from prospectively enrolled sepsis patients (first 24 hr) and a zebrafish endotoxemia model for drug discovery. Patients were enrolled from the emergency department or ICU at an urban teaching hospital. Enrollment samples from sepsis patients were analyzed. Clinical data and cholesterol levels were recorded. Leukocytes were processed for RNA sequencing and reverse transcriptase polymerase chain reaction. A lipopolysaccharide zebrafish endotoxemia model was used for confirmation of human transcriptomic findings and drug discovery. MAIN OUTCOMES AND MEASURES:The derivation cohort included 96 patients and controls (12 early death, 13 CCI, 51 rapid recovery, and 20 controls) and the validation cohort had 52 patients (6 early death, 8 CCI, and 38 rapid recovery). RESULTS:The cholesterol metabolism gene 7-dehydrocholesterol reductase (DHCR7) was significantly up-regulated in both derivation and validation cohorts in poor outcome sepsis compared with rapid recovery patients and in 90-day nonsurvivors (validation only) and validated using RT-qPCR analysis. Our zebrafish sepsis model showed up-regulation of dhcr7 and several of the same lipid genes up-regulated in poor outcome human sepsis (dhcr24, sqlea, cyp51, msmo1, and ldlra) compared with controls. We then tested six lipid-based drugs in the zebrafish endotoxemia model. Of these, only the Dhcr7 inhibitor AY9944 completely rescued zebrafish from lipopolysaccharide death in a model with 100% lethality. CONCLUSIONS: DHCR7, an important cholesterol metabolism gene, was upregulated in poor outcome sepsis patients warranting external validation. This pathway may serve as a potential therapeutic target to improve sepsis outcomes.

Lipidomic changes in a novel sepsis outcome‐based analysis reveals potent pro‐inflammatory and pro‐resolving signaling lipids

“…For this analysis, 262 patients with sepsis samples were included, with 189 rapid recovery, 45 CCI, and 28 early death (Table 3). As with the lipidomic analysis, the CCI and early death groups were combined for analysis as in prior studies 27 . We detected many pro‐inflammatory signaling lipids from ω‐6 PUFAs, including 9‐,13‐HODE and 5‐,11‐, 12‐, and 15‐hydroxyeicosatetraenoic (HETE), along with pro‐resolving lipid mediators 14(S)‐hydroxy docosahexaenoic acid (14S‐HDHA) and Resolving D1 (RVD1) derived from ω‐3 PUFAs (Table 3).…”

“…As with the lipidomic analysis, the CCI and early death groups were combined for analysis as in prior studies. 27 We detected many pro-inflammatory signaling lipids from ω-6 PUFAs, including 9-,13-HODE and 5-,11-, 12-, and 15-hydroxyeicosatetraenoic (HETE), along with proresolving lipid mediators 14(S)-hydroxy docosahexaenoic acid (14S-HDHA) and Resolving D1 (RVD1) derived from ω-3 PUFAs (Table 3). There were multiple analytes significantly increased in this analysis (Table 3).…”

Chemical Inhibition of Sterol Biosynthesis

“…Although prolonged DHCR7 alterations tend to result in negative outcomes, mimicking SLOS, short-term alterations during periods of stress may be protective. For example, Dhcr7 mRNA has been found to be upregulated in the leukocytes of those with sepsis who have poor outcome, while inhibiting DHCR7 with AY9944 in zebrafish exposed to LPS decreased lethality [48]. The exact mechanism of this protection is still being evaluated, but the benefits of short-term AY9944 appear to be consistent across several disease models.…”