Daily Endocrinology Research Analysis

BACKGROUND: While low levels of LDL-cholesterol can be atheroprotective, homozygous Class I familial hypobetalipoproteinemia (Ho-Class I FHBL) and heterozygous Class I FHBL (He-Class I FHBL) due to APOB variants (i.e., heterozygous FHBL1 (HeFHBL1)) have serious complications due to genetic defects in the chylomicron/VLDL secretion pathway. However, Ho-Class I FHBL with milder phenotypes and HeFHBL1 are often underdiagnosed due to overlapping lipid profiles with other forms of hypobetalipoproteinemia. OBJECTIVE: Additional screening markers are warranted. METHODS: We established a prospective HBL cohort and performed detailed genotype-phenotype analyses to identify biomarkers associated with Class I FHBL. For further exploration, we systematically reviewed cases with Class I FHBL. RESULTS: In our lipid genome cohort (n = 440), whole-exome sequencing of 18 consecutive cases of HBL (LDL-C <30 mg/dL) identified 7 novel pathogenic variants in 7 cases of Class I FHBL. Genotype-phenotype analyses revealed that plasma vitamin K1 is the strongest independent predictor of Class I FHBL. The vitamin K1 levels in HeFHBL1 were significantly reduced by approximately 50% compared to controls, reflecting the half-normal lipoprotein secretion. Systematic review analyses (n = 472) revealed that vitamin K1 is the only fat-soluble vitamin that is significantly decreased not only in Ho-Class I FHBL but also in HeFHBL1. CONCLUSION: Plasma vitamin K1 may serve as a sensitive screening marker of fat malabsorption, facilitating the genetic diagnosis of Class I FHBL, enabling early management of its complications, such as fat malabsorption, fat-soluble vitamin deficiency, potential vitamin K deficiency, and steatotic liver disease.

BACKGROUND: Sex hormones and HIV infection both influence cardiovascular health. However, the association between sex hormones and subclinical atherosclerosis is not fully understood, especially in the context of HIV. METHODS: Among 321 men (65% with HIV) from the MACS/WIHS Combined Cohort Study, we measured 14 serum sex hormones and sex hormone-binding globulin (SHBG), assessed carotid artery plaque (IMT > 1.5 mm) using high-resolution B-mode ultrasound, and performed metagenomic sequencing on stool samples. In 312 men, we measured 986 plasma metabolites via liquid chromatography-tandem mass spectrometry and 2883 plasma proteins using the Olink Explore 3072 platform. In stratified analyses of men with (MWH) and without HIV (MWOH) and adjusting for covariates and multiple testing, we (1) examined associations of sex hormones with plaque; (2) characterized multi-omics profiles related to sex hormones; and (3) generated sex hormone-related omics scores via linear combination of related species, metabolites, and proteins, respectively, to explore whether these sex hormone-related multi-omics profiles were associated with plaque. RESULTS: Median age of participants was 62 years (interquartile range: 58-68), and 31.5% had carotid artery plaque. Sex hormones were differentially associated with plaque in MWH and MWOH. In MWH, an inverse association was observed between SHBG and plaque (OR = 0.60 per 1-SD increase, 95% CI: 0.41, 0.90). Furthermore, higher SHBG levels were associated with overall gut microbial composition, lower abundance of species from genera Prevotella, Fibrobacter and Coprococcus, higher levels of certain metabolites (primarily lipid and carnitine metabolites) and proteins enriched in the cell-cell adhesion pathway. Some SHBG-related species (e.g., Mediterranea massiliensis), metabolites (e.g., phosphatidylcholine-based lipids) and proteins (e.g., enriched in immune response pathway) were also associated with plaque in MWH. All three SHBG-related omics scores were inter-correlated and inversely associated with plaque in MWH. In MWOH, estrone-sulfate was positively associated with plaque (OR = 3.80, 95% CI: 1.41, 10.22) but not with any species, metabolites or proteins. CONCLUSIONS: Higher SHBG, and related microbial species, circulating metabolites, and proteins, were inversely associated with carotid artery plaque. These findings suggested that SHBG may play a protective role in subclinical atherosclerosis in MWH.

RATIONALE AND OBJECTIVES: To characterize liver fat distribution in metabolic dysfunction-associated steatohepatitis (MASH) and propose a magnetic resonance imaging proton density fat fraction (MRI-PDFF)-based score for MASH identification in obesity. MATERIALS AND METHODS: Individuals with obesity were recruited for liver biopsy and contemporaneous MR scanning. The variability in fat distribution was evaluated by calculating the standard deviation (SD), range, and coefficient of variation of MRI-PDFF across liver lobes. A machine learning-assisted strategy was employed to establish a diagnostic model for MASH. RESULTS: A total of 107 participants with biopsy-confirmed fatty liver were included, and 44 were diagnosed with MASH. The MASH group exhibited significantly higher fat content in all liver segments and more homogeneous fat distribution in the right liver lobe than those with non-MASH. A raw-MASH score, incorporating the mean value and SD of PDFF in the right lobe, alanine aminotransferase levels, and waist circumference, was then established to identify MASH with an area under the receiver operating characteristic curve (AUROC) of 0.90 (95%CI 0.84-0.95). It performed better than HAIR, ION, and acNASH (all p < 0.05), and exhibited higher AUROC than MR-MASH model (0.90 vs. 0.85, p = 0.066). Besides, the dual threshold strategy of raw-MASH improved the diagnostic performance with high sensitivity and specificity. CONCLUSION: In addition to the hepatic fat content, the homogeneity of fat distribution may represent another significant hallmark of MASH. The raw-MASH score, which is available from MR imaging and routine clinical collection, shows great potential for identifying MASH in obesity.