Diurnal Variation of Markers for Cholesterol Synthesis, Cholesterol Absorption, and Bile Acid Synthesis:A Systematic Review and the Bispebjerg Study of Diurnal Variations

Human studies have shown diurnal rhythms of cholesterol and bile acid synthesis, but a better understanding of the role of the circadian system in cholesterol homeostasis is needed for the development of targeted interventions to improve metabolic health. Therefore, we performed a systematic literature search on the diurnal rhythms of cholesterol synthesis and absorption markers and of bile acid synthesis markers. We also examined the diurnal rhythms of the cholesterol synthesis markers lathosterol and desmosterol, and of the cholesterol absorption markers cholestanol, campesterol, and sitosterol in serum samples from the Bispebjerg study. These samples were collected every three hours over a 24-h period in healthy males (n = 24) who consumed low-fat meals. The systematic search identified sixteen papers that had examined the diurnal rhythms of the cholesterol synthesis markers lathosterol (n = 3), mevalonate (n = 9), squalene (n = 2), or the bile acid synthesis marker 7 alpha-hydroxy-4-cholesten-3-one (C4) (n = 4). Results showed that lathosterol, mevalonate, and squalene had a diurnal rhythm with nocturnal peaks, while C4 had a diurnal rhythm with daytime peaks. Furthermore, cosinor analyses of the serum samples showed a significant diurnal rhythm for lathosterol (cosinor p 0.05). In conclusion, cholesterol synthesis and bile acid synthesis have a diurnal rhythm, though no evidence for a diurnal rhythm of cholesterol absorption was found under highly standardised conditions. More work is needed to further explore the influence of external factors on the diurnal rhythms regulating cholesterol homeostasis

Cosmic Star Formation History and its Dependence on Galaxy Stellar Mass

We examine the cosmic star formation rate (SFR) and its dependence on galaxy stellar mass over the redshift range 0.8 < z < 2 using data from the Gemini Deep Deep Survey (GDDS). The SFR in the most massive galaxies (M > 10^{10.8} M_sun) was six times higher at z = 2 than it is today. It drops steeply from z = 2, reaching the present day value at z ~ 1. In contrast, the SFR density of intermediate mass galaxies (10^{10.2} < M < 10^{10.8} M_sun) declines more slowly and may peak or plateau at z ~ 1.5. We use the characteristic growth time t_SFR = rho_M / rho_SFR to provide evidence of an associated transition in massive galaxies from a burst to a quiescent star formation mode at z ~ 2. Intermediate mass systems transit from burst to quiescent mode at z ~ 1, while the lowest mass objects undergo bursts throughout our redshift range. Our results show unambiguously that the formation era for galaxies was extended and proceeded from high to low mass systems. The most massive galaxies formed most of their stars in the first ~3 Gyr of cosmic history. Intermediate mass objects continued to form their dominant stellar mass for an additional ~2 Gyr, while the lowest mass systems have been forming over the whole cosmic epoch spanned by the GDDS. This view of galaxy formation clearly supports `downsizing' in the SFR where the most massive galaxies form first and galaxy formation proceeds from larger to smaller mass scales.Comment: Accepted for publication in ApJ

Red Nuggets at z~1.5: Compact passive galaxies and the formation of the Kormendy Relation

We present the results of NICMOS imaging of a sample of 16 high mass passively evolving galaxies with 1.3<z<2, taken primarily from the Gemini Deep Deep Survey. Around 80% of galaxies in our sample have spectra dominated by stars with ages >1 Gyr. Our rest-frame R-band images show that most of these objects have compact regular morphologies which follow the classical R^1/4 law. These galaxies scatter along a tight sequence in the Kormendy relation. Around one-third of the massive red objects are extraordinarily compact, with effective radii under one kiloparsec. Our NICMOS observations allow the detection of such systems more robustly than is possible with optical (rest-frame UV) data, and while similar systems have been seen at z>2, this is the first time such systems have been detected in a rest-frame optical survey at 1.3<z<2. We refer to these compact galaxies as "red nuggets". Similarly compact massive galaxies are completely absent in the nearby Universe. We introduce a new "stellar mass Kormendy relation" (stellar mass density vs size) which isolates the effects of size evolution from those of luminosity and color evolution. The 1.1 < z < 2 passive galaxies have mass densities that are an order of magnitude larger then early type galaxies today and are comparable to the compact distant red galaxies at 2 < z < 3. We briefly consider mechanisms for size evolution in contemporary models focusing on equal-mass mergers and adiabatic expansion driven by stellar mass loss. Neither of these mechanisms appears able to transform the high-redshift Kormendy relation into its local counterpart. Comment: Accepted version (to appear in ApJ

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. Homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC), in contrast to patients with two predicted protein truncating mutations (PPTM). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n=31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n=30), and with two PPTMs (BSEP3/3; n=77). We compared presentation, native liver survival (NLS), and effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (P<0.001). Without siEHC in their follow-up, NLS of BSEP1/3 was similar to BSEP3/3 patients, but considerably lower than BSEP1/1 patients (at age 10 years: 38%, 30%, and 71%, resp; P=0.003). After siEHC, BSEP1/3 and BSEP3/3 patients had similarly low NLS, while this was much higher in BSEP1/1 patients (10 years after siEHC, 27%, 14%, and 92%, resp.; P<0.001). Conclusions: BSEP deficiency patients with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as patients with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways