Fat Quantification in Dual-Layer Detector Spectral Computed Tomography: Experimental Development and First In-Patient Validation.

OBJECTIVES: Fat quantification by dual-energy computed tomography (DECT) provides contrast-independent objective results, for example, on hepatic steatosis or muscle quality as parameters of prognostic relevance. To date, fat quantification has only been developed and used for source-based DECT techniques as fast kVp-switching CT or dual-source CT, which require a prospective selection of the dual-energy imaging mode.It was the purpose of this study to develop a material decomposition algorithm for fat quantification in phantoms and validate it in vivo for patient liver and skeletal muscle using a dual-layer detector-based spectral CT (dlsCT), which automatically generates spectral information with every scan. MATERIALS AND METHODS: For this feasibility study, phantoms were created with 0%, 5%, 10%, 25%, and 40% fat and 0, 4.9, and 7.0 mg/mL iodine, respectively. Phantom scans were performed with the IQon spectral CT (Philips, the Netherlands) at 120 kV and 140 kV and 3 T magnetic resonance (MR) (Philips, the Netherlands) chemical-shift relaxometry (MRR) and MR spectroscopy (MRS). Based on maps of the photoelectric effect and Compton scattering, 3-material decomposition was done for fat, iodine, and phantom material in the image space.After written consent, 10 patients (mean age, 55 ± 18 years; 6 men) in need of a CT staging were prospectively included. All patients received contrast-enhanced abdominal dlsCT scans at 120 kV and MR imaging scans for MRR. As reference tissue for the liver and the skeletal muscle, retrospectively available non-contrast-enhanced spectral CT data sets were used. Agreement between dlsCT and MR was evaluated for the phantoms, 3 hepatic and 2 muscular regions of interest per patient by intraclass correlation coefficients (ICCs) and Bland-Altman analyses. RESULTS: The ICC was excellent in the phantoms for both 120 kV and 140 kV (dlsCT vs MRR 0.98 [95% confidence interval (CI), 0.94-0.99]; dlsCT vs MRS 0.96 [95% CI, 0.87-0.99]) and in the skeletal muscle (0.96 [95% CI, 0.89-0.98]). For log-transformed liver fat values, the ICC was moderate (0.75 [95% CI, 0.48-0.88]). Bland-Altman analysis yielded a mean difference of -0.7% (95% CI, -4.5 to 3.1) for the liver and of 0.5% (95% CI, -4.3 to 5.3) for the skeletal muscle. Interobserver and intraobserver agreement were excellent (>0.9). CONCLUSIONS: Fat quantification was developed for dlsCT and agreement with MR techniques demonstrated for patient liver and muscle. Hepatic steatosis and myosteatosis can be detected in dlsCT scans from clinical routine, which retrospectively provide spectral information independent of the imaging mode.

Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport.

Brown and beige adipocytes combust nutrients for thermogenesis and through their metabolic activity decrease pro-atherogenic remnant lipoproteins in hyperlipidemic mice. However, whether the activation of thermogenic adipocytes affects the metabolism and anti-atherogenic properties of high-density lipoproteins (HDL) is unknown. Here, we report a reduction in atherosclerosis in response to pharmacological stimulation of thermogenesis linked to increased HDL levels in APOE*3-Leiden.CETP mice. Both cold-induced and pharmacological thermogenic activation enhances HDL remodelling, which is associated with specific lipidomic changes in mouse and human HDL. Furthermore, thermogenic stimulation promotes HDL-cholesterol clearance and increases macrophage-to-faeces reverse cholesterol transport in mice. Mechanistically, we show that intravascular lipolysis by adipocyte lipoprotein lipase and hepatic uptake of HDL by scavenger receptor B-I are the driving forces of HDL-cholesterol disposal in liver. Our findings corroborate the notion that high metabolic activity of thermogenic adipocytes confers atheroprotective properties via increased systemic cholesterol flux through the HDL compartment.

Liver TAG transiently decreases while PL n-3 and n-6 fatty acids are persistently elevated in insulin resistant mice.

Changes in fatty acid metabolism associated with insulin resistance have been described in rats and humans but have not been well characterized in the frequently used mouse model of diet-induced obesity. To analyse the early phase as well as established insulin resistance, C57BL/6 mice were placed for 1 or 16 weeks on a high fat diet (1w-HFD, 16w-HFD). Endocrine and metabolic parameters indicated that 1w-HFD mice showed a moderate but significant induction of insulin resistance while 16w-HFD mice exhibited profound obesity-associated insulin resistance and dyslipidemias. Significant alterations in fatty acid composition were observed in plasma and liver in both groups. Liver phospholipid-associated arachidonate and docosahexaenoate were increased in both 1w-HFD and 16w-HFD mice, possibly due to increased expression of the desaturases Fads1 and Fads2. Unexpectedly, SCD1 activity and gene expression in liver were decreased in the 1w-HFD group accompanied by diminished total hepatic lipid levels, while they were increased in chronically fed mice. Our data indicate that the early phase of HFD-induced insulin resistance is not associated with elevated liver lipid concentration. Furthermore, the early and persistent rise of arachidonate and docosahexaenoate indicates that insulin resistance is not due to insufficient availability (or concentrations) of polyunsaturated fatty acids as postulated previously.

Expression of LRP1 by human osteoblasts: a mechanism for the delivery of lipoproteins and vitamin K1 to bone.

UNLABELLED: Accumulating clinical and experimental data show the importance of dietary lipids and lipophilic vitamins, such as vitamin K1, for bone formation. The molecular mechanism of how they enter the osteoblast is unknown. Here we describe the expression of the multifunctional LRP1 by human osteoblasts in vitro and in vivo. We provide evidence that LRP1 plays an important role in the uptake of postprandial lipoproteins and vitamin K1 by human osteoblasts. INTRODUCTION: Chylomicrons (CM) and their remnants (CR) represent the postprandial plasma carriers of dietary lipids. Dietary vitamin K1 is known to be transported in the circulation as part of CM/CR and is required by osteoblasts as an essential co-factor for the gamma-carboxylation of bone matrix proteins. The molecular mechanisms underlying the delivery of lipophilic substances to bone are not understood. In this study, the expression and function of CM/CR receptors was examined in human osteoblasts. MATERIALS AND METHODS: Four human osteoblast-like cell lines were analyzed: two osteosarcoma lines (MG63, SaOS-2) and two telomerase-immortalized human bone marrow stromal cell lines (hMSC-TERT [4] and [20]) after 1,25(OH)2 vitamin D3 induction of osteoblastic differentiation (hMSC-TERT-OB). Receptor expression was examined by Western blotting and immunohistochemistry of normal human bone sections. Endocytotic receptor function was analyzed by cellular uptake assays using fluorescent and radiolabeled human CR. Vitamin K1-enriched CR (CR-K1) were generated in vivo after oral vitamin administration and vitamin K1 uptake by osteoblasts was measured by HPLC. The effect of CR-K1 uptake on osteocalcin carboxylation was measured by ELISA. RESULTS: Osteoblasts exhibit high levels of protein expression of the CR receptors LRP1 and LDLR. VLDLR is expressed to a lower degree. Immunohistochemistry of normal human bone sections showed strong LRP1 expression by osteoblasts and marrow stromal cells. Uptake of fluorescent CR by osteoblasts resulted in the typical pattern of receptor-mediated endocytosis. CR uptake was stimulated by the exogenous addition of the lipoprotein receptor ligands apolipoprotein E and lipoprotein lipase. Uptake was reduced by the known LRP1 inhibitors RAP, lactoferrin, and suramin, but not by LDL, which exclusively binds to the LDLR. Vitamin K1 uptake by hMSC-TERT-OB after incubation with CR-K1 was also shown to be sensitive to LPL stimulation and the LRP1 specific inhibitor lactoferrin. CR-K1 uptake into osteoblasts stimulated the gamma-carboxylation of osteocalcin. CONCLUSION: Human osteoblasts express receptors of the LDLR family with a capacity for vitamin K1 uptake through CR endocytosis, a novel mechanism for the delivery of dietary lipids and lipophilic vitamins to human bone. The current data suggest that, among the expressed receptors, LRP1 plays a predominant role.