The Cholesterol Metabolite Cholest-5-en-3-One Alleviates Hyperglycemia and Hyperinsulinemia in Obese (db/db) Mice

Dietary sterols are catabolized into various substances in the intestinal tract. Dietary 3-oxo derivatives of cholesterol and plant sterols (e.g., cholest-4-en-3-one and campest-5-en-3-one) have been shown to have anti-obesity effects. In this study, we tested whether feeding cholest-5-en-3-one (5-cholestenone), a cholesterol metabolite, to db/db mice protects them from obesity-associated metabolic disorders. In db/db mice, dietary 5-cholestenone significantly alleviated hepatomegaly and elevated serum triglyceride levels; however, the effect was not sufficient to improve hepatic steatosis and obesity. On the other hand, hyperglycemia and severe hyperinsulinemia in control db/db mice were markedly attenuated in 5-cholestenone-fed db/db mice. The production of inflammatory cytokines, such as monocyte chemoattractant protein-1, interleukin-6, and tumor necrosis factor-alpha (TNFα), was decreased, suggesting that the suppressive actions of 5-cholestenone were attributable to the alleviation of chronic inflammation in db/db mice. Additionally, 5-cholestenone showed an inhibitory effect on TNFα-induced nuclear factor kappa B (NFκB) activation in the NFκB luciferase gene reporter assay. These results suggest that obesity-induced abnormal glucose metabolism could be alleviated in 5-cholestenone-fed db/db mice by reducing the production of inflammatory cytokines through suppression of the NFκB signaling pathway.

Drosophila melanogaster females prioritise dietary sterols for producing high quality eggs

Limiting calories or specific nutrients without malnutrition, otherwise known as dietary restriction (DR), has been shown to extend lifespan across a broad range of taxa. Our recent findings in Drosophila melanogaster show that supplementing flies on macronutrient-rich diets with additional cholesterol can extend lifespan to the same extent as DR. Macronutrient-rich diets drive high levels of egg production and in doing so deplete the mothers of somatic sterols that are essential for survival. Thus, DR may be beneficial for lifespan because it reduces egg production which in turn reduces the mother's demand for sterols. If this is true, mothers must be prioritising their available sterols, whether from the diet or from their own bodies, to sustain high quality egg production. To test this, we measured the quality of eggs laid by mothers fed either cholesterol-sufficient or cholesterol-depleted diets. We found that even when the mother's diet was completely devoid of cholesterol, high quality egg production persisted. Furthermore, we show that sterol-supplemented flies with long lives continue to lay high quality eggs that give rise to healthy offspring. Thus, in our assays, long life does not require a fecundity cost.

Sitosterolemia: A Rare Case with Broad Implications

Sitosterolemia is an ultra-rare autosomal recessive dyslipidemia characterized by mutations in genes encoding the ATP-binding cassette (ABC) G5/8 transporters. We describe the case of a 20-month-old female presenting with xanthomas and serum low density lipoprotein cholesterol of 657 mg/dL. Diagnostic workup revealed a previously undescribed sitosterolemia-causing mutation. After elimination of dietary sterols and initiation of ezetimibe therapy, the patient’s xanthomas resolved, and serum low density lipoprotein cholesterol was reduced to 104 mg/dL. Importantly, pathologically elevated serum phytosterols were found in each of the proband’s heterozygous parents. Elevated phytosterols, an established cause of atherosclerosis, are typically unrevealed by standard lipid testing. As heterozygous mutations for ABCG5/8 are relatively common, this has implications for a broader population than the ultra-rare sitosterolemia cohort. Thus, insights gleaned from this case highlight underappreciated matters in the prevention of atherosclerotic disease in both heterozygous and homozygous carriers alike.

A dietary sterol trade-off determines lifespan responses to dietary restriction in Drosophila melanogaster females

Diet plays a significant role in maintaining lifelong health. In particular, lowering the dietary protein: carbohydrate ratio can improve lifespan. This has been interpreted as a direct effect of these macronutrients on physiology. Using Drosophila melanogaster, we show that the role of protein and carbohydrate on lifespan is indirect, acting by altering the partitioning of limiting amounts of dietary sterols between reproduction and lifespan. Shorter lifespans in flies fed on high protein: carbohydrate diets can be rescued by supplementing their food with cholesterol. Not only does this fundamentally alter the way we interpret the mechanisms of lifespan extension by dietary restriction, these data highlight the important principle that life histories can be affected by nutrient-dependent trade-offs that are indirect and independent of the nutrients (often macronutrients) that are the focus of study. This brings us closer to understanding the mechanistic basis of dietary restriction.

A dietary sterol trade off determines lifespan responses to dietary restriction in Drosophila melanogaster

Diet plays a significant role in maintaining lifelong health. In particular, lowering the dietary protein : carbohydrate ratio can improve lifespan. This has been interpreted as a direct effect of these macronutrients on physiology. Using Drosophila melanogaster, we show that the role of protein and carbohydrate on lifespan is indirect, acting by altering the partitioning of limiting amounts of dietary sterols between reproduction and lifespan. Shorter lifespans in flies fed on high protein : carbohydrate diets can be rescued by supplementing their food with cholesterol. Not only does this fundamentally alter the way we interpret the mechanisms of lifespan extension by dietary restriction, these data highlight the important principle that life histories can be affected by nutrient-dependent trade-offs that are indirect and independent of the nutrients (often macronutrients) that are the focus of study. This brings us closer to understanding the mechanistic basis of dietary restriction.

Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease

Aims To explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols. Methods and results We examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk [odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75–2.31, P = 9.8 × 10−23] compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49–1.59, P = 1.1 × 10−154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10−4). Conclusions Genetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis.

Insect Sterol Nutrition: Physiological Mechanisms, Ecology, and Applications

Insects, like all eukaryotes, require sterols for structural and metabolic purposes. However, insects, like all arthropods, cannot make sterols. Cholesterol is the dominant tissue sterol for most insects; insect herbivores produce cholesterol by metabolizing phytosterols, but not always with high efficiency. Many insects grow on a mixed-sterol diet, but this ability varies depending on the types and ratio of dietary sterols. Dietary sterol uptake, transport, and metabolism are regulated by several proteins and processes that are relatively conserved across eukaryotes. Sterol requirements also impact insect ecology and behavior. There is potential to exploit insect sterol requirements to ( a) control insect pests in agricultural systems and ( b) better understand sterol biology, including in humans. We suggest that future studies focus on the genetic mechanism of sterol metabolism and reverse transportation, characterizing sterol distribution and function at the cellular level, the role of bacterial symbionts in sterol metabolism, and interrupting sterol trafficking for pest control.

Evaluating Effects of a Critical Micronutrient (24-Methylenecholesterol) on Honey Bee Physiology

Although poor nutrition is cited as one of the crucial factors in global pollinator decline, the requirements and role of several important nutrients (especially micronutrients) in honey bees are not well understood. Micronutrients, viz. phytosterols, play a physiologically vital role in insects as precursors of important molting hormones and building blocks of cellular membranes. There is a gap in comprehensive understanding of the impacts of dietary sterols on honey bee physiology. In the present study, we investigated the role of 24-methylenecholesterol—a key phytosterol—in honey bee nutritional physiology. Artificial diets with varying concentrations of 24-methylenecholesterol (0%, 0.1%. 0.25%, 0.5%, 0.75%, and 1% dry diet weight) were formulated and fed to honey bees in a laboratory cage experiment. Survival, diet consumption, head protein content, and abdominal lipid contents were significantly higher in dietary sterol-supplemented bees. Our findings provide additional insights regarding the role of this important sterol in honey bee nutritional physiology. The insights gleaned from this study could also advance the understanding of sterol metabolism and regulation in other bee species that are dependent on pollen for sterols, and assist in formulation of a more complete artificial diet for honey bees (Apis mellifera Linnaeus, 1758) (Hymenoptera: Apidae).