The liver is a vital organ that regulates systemic energy metabolism and many physiological functions. Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease and end-stage liver failure. NAFLD is primarily caused by metabolic disruption of lipid and glucose homeostasis. Serotonin (5-hydroxytryptamine [5-HT]) is a biogenic amine with several functions in both the central and peripheral systems. 5-HT functions as a neurotransmitter in the brain and a hormone in peripheral tissues to regulate systemic energy homeostasis. Several recent studies have proposed various roles of 5-HT in hepatic metabolism and inflammation using tissue-specific knockout mice and 5-HT-receptor agonists/antagonists. This review compiles the most recent research on the relationship between 5-HT and hepatic metabolism, and the role of 5-HT signaling as a potential therapeutic target in NAFLD.

Although age-related changes in skeletal muscles are closely associated with decreases in muscle strength and functional decline, their associations with cardiometabolic diseases in the literature are inconsistent. Such inconsistency could be explained by the fact that muscle quality―which is closely associated with fatty infiltration of the muscle (i.e., myosteatosis)―is as important as muscle quantity in cardiometabolic health. However, muscle quality has been less explored compared with muscle mass. Moreover, the standard definition of myosteatosis and its assessment methods have not been established yet. Recently, some techniques using single axial computed tomography (CT) images have been introduced and utilized in many studies, as the mass and quality of abdominal muscles could be measured opportunistically on abdominal CT scans obtained during routine clinical care. Yet, the mechanisms by which myosteatosis affect metabolic and cardiovascular health remain largely unknown. In this review, we explore the recent advances in the assessment of myosteatosis and its changes associated with aging. We also review the recent literature on the clinical implication of myosteatosis by focusing on metabolic and cardiovascular diseases. Finally, we discuss the challenges and unanswered questions that need addressing to set myosteatosis as a therapeutic target for the prevention or treatment of cardiometabolic diseases.

Background: In South Korea, women aged 66 years are eligible for complimentary bone mineral density (BMD) screening via the National Screening Program for Transitional Ages. We aimed to evaluate the 10-year fracture risk in women receiving BMD screening between January 2008 and December 2015.
Methods: BMD was classified as normal (T-score ≥-1.0 standard deviation [SD]), osteopenia (T-score < -1.0 SD and >-2.5 SD), and osteoporosis (T score ≤-2.5 SD) from dual-energy X-ray absorptiometry. Follow-up continued from the screening date until a diagnosis for clinical fragility fracture (including sites of the vertebrae, hip, pelvis, clavicle, humerus, forearm, wrist, lower leg, and ankle), censored at the earliest date of trauma, death, or December 2017; fracture was ascertained using diagnostic codes from the National Health Insurance Service database. A multivariable Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of fracture in women with osteopenia or osteoporosis relative to women with normal BMD.
Results: Among the 271,197 women screened, 44.0% had osteopenia and 35.2% had osteoporosis. The 10 year cumulative incidence of fragility fractures was 31.1%, 37.5%, and 44.3% in women with normal BMD, osteopenia, and osteoporosis, respectively. Fracture risk was higher in women with osteopenia (HR, 1.31; 95% CI, 1.28 to 1.34) and osteoporosis (HR, 1.68; 95% CI, 1.64 to 1.72) than in women with normal BMD.
Conclusion: Women with osteopenia and women with osteoporosis, identified by the national BMD screening program, demonstrated a substantially elevated risk of fracture.

Background: Epidemiological data have shown that vitamin D deficiency is highly prevalent in Korea. Genetic factors influencing vitamin D deficiency in humans have been studied in Europe but are less known in East Asian countries, including Korea. We aimed to investigate the genetic factors related to vitamin D levels in Korean people using a genome-wide association study (GWAS).
Methods: We included 12,642 subjects from three different genetic cohorts consisting of Korean participants. The GWAS was performed on 7,590 individuals using linear or logistic regression meta- and mega-analyses. After identifying significant single nucleotide polymorphisms (SNPs), we calculated heritability and performed replication and rare variant analyses. In addition, expression quantitative trait locus (eQTL) analysis for significant SNPs was performed.
Results: rs12803256, in the actin epsilon 1, pseudogene (ACTE1P) gene, was identified as a novel polymorphism associated with vitamin D deficiency. SNPs, such as rs11723621 and rs7041, in the group-specific component gene (GC) and rs11023332 in the phosphodiesterase 3B (PDE3B) gene were significantly associated with vitamin D deficiency in both meta- and mega-analyses. The SNP heritability of the vitamin D concentration was estimated to be 7.23%. eQTL analysis for rs12803256 for the genes related to vitamin D metabolism, including glutamine-dependent NAD(+) synthetase (NADSYN1) and 7-dehydrocholesterol reductase (DHCR7), showed significantly different expression according to alleles.
Conclusion: The genetic factors underlying vitamin D deficiency in Korea included polymorphisms in the GC, PDE3B, NADSYN1, and ACTE1P genes. The biological mechanism of a non-coding SNP (rs12803256) for DHCR7/NADSYN1 on vitamin D concentrations is unclear, warranting further investigations.

Background: A decrease in computed tomography (CT)-derived skeletal muscle radiodensity (SMD) reflects age-related ectopic fat infiltration of muscle, compromising muscle function and metabolism. We investigated the age-related trajectory of SMD and its association with vertebral trabecular bone density in healthy adults.
Methods: In a cohort of healthy adult kidney donors aged 19 to 69 years (n=583), skeletal muscle index (SMI, skeletal muscle area/height2), SMD, and visceral-to-subcutaneous fat (V/S) ratio were analyzed at the level of L3 from preoperative CT scans. Low bone mass was defined as an L1 trabecular Hounsfield unit (HU) <160 HU.
Results: L3SMD showed constant decline from the second decade (annual change -0.38% and -0.43% in men and women), whereas the decline of L3SMI became evident only after the fourth decade of life (-0.37% and -0.18% in men and women). One HU decline in L3SMD was associated with elevated odds of low bone mass (adjusted odds ratio, 1.07; 95% confidence interval, 1.02 to 1.13; P=0.003), independent of L3SMI, age, sex, and V/S ratio, with better discriminatory ability compared to L3SMI (area under the receiver-operating characteristics curve 0.68 vs. 0.53, P<0.001). L3SMD improved the identification of low bone mass when added to age, sex, V/S ratio, and L3SMI (category-free net reclassification improvement 0.349, P<0.001; integrated discrimination improvement 0.015, P=0.0165).
Conclusion: L3SMD can be an early marker for age-related musculoskeletal changes showing linear decline throughout life from the second decade in healthy adults, with potential diagnostic value for individuals with low bone mass.

Background: Dickkopf-1 (DKK1) regulates bone formation by inhibiting canonical Wnt/β-catenin pathway signaling, and indirectly enhances osteoclastic activity by altering the expression ratio of receptor activator of nuclear factor-κB ligand (RANKL) relative to osteoprotegerin (OPG). However, it is difficult to explain continued bone loss after allogeneic stem cell transplantation (allo-SCT) in terms of changes in only RANKL and OPG. Few studies have evaluated changes in DKK1 after allo-SCT.
Methods: We prospectively enrolled 36 patients with hematologic malignancies who were scheduled for allo-SCT treatment. Serum DKK1, OPG, and RANKL levels were measured before (baseline), and at 1, 4, 12, 24, and 48 weeks after allo-SCT treatment. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry before (baseline) and 24 and 48 weeks after allo-SCT treatment.
Results: After allo-SCT treatment, the DKK1 level decreased rapidly, returned to baseline during the first 4 weeks, and remained elevated for 48 weeks (P<0.0001 for changes observed over time). The serum RANKL/OPG ratio peaked at 4 weeks and then declined (P<0.001 for changes observed over time). BMD decreased relative to the baseline at all timepoints during the study period, and the lumbar spine in female patients had the largest decline (-11.3%±1.6% relative to the baseline at 48 weeks, P<0.05).
Conclusion: Serum DKK1 levels rapidly decreased at 1 week and then continued to increase for 48 weeks; bone mass decreased for 48 weeks following engraftment in patients treated with allo-SCT, suggesting that DKK1-mediated inhibition of osteoblast differentiation plays a role in bone loss in patients undergoing allo-SCT.

Background: Dual-energy X-ray absorptiometry (DXA) is the most widely used method for evaluating muscle masses. The aim of this study was to investigate the agreement between muscle mass values assessed by two different DXA systems.
Methods: Forty healthy participants (20 men, 20 women; age range, 23 to 71 years) were enrolled. Total and regional body compositional values for fat and lean masses were measured consecutively with two DXA machines, Hologic Horizon and GE Lunar Prodigy. Appendicular lean mass (ALM) was calculated as the sum of the lean mass of four limbs.
Results: In both sexes, the ALM values measured by the GE Lunar Prodigy (24.8±4.3 kg in men, 15.8±2.9 kg in women) were significantly higher than those assessed by Hologic Horizon (23.0±4.0 kg in men, 14.8±3.2 kg in women). Furthermore, BMI values or body fat (%), either extremely higher or lower levels, contributed greater differences between two systems. Bland-Altman analyses revealed a significant bias between ALM values assessed by the two systems. Linear regression analyses were performed to develop equations to adjust for systematic differences (men: Horizon ALM [kg]=0.915×Lunar Prodigy ALM [kg]+0.322, R2=0.956; women: Horizon ALM [kg]=1.066×Lunar Prodigy ALM [kg]-2.064, R2=0.952).
Conclusion: Although measurements of body composition including muscle mass by the two DXA systems correlated strongly, significant differences were observed. Calibration equations should enable mutual conversion between different DXA systems.

Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) has rapidly increased worldwide. The aim of this study was to investigate whether there is an independent relationship between regional fat distribution, especially leg fat mass, and the presence of NAFLD using nationally representative data in Korea.
Methods: This cross-sectional study analyzed data from 14,502 participants in the Korea National Health and Nutrition Examination Survey 2008 to 2011. Total fat mass, leg fat mass, and appendicular skeletal muscle mass were measured by dual-energy X-ray absorptiometry. Validated NAFLD prediction models and scoring systems for hepatic fibrosis were used.
Results: The leg fat to total fat (LF/TF) ratio showed a negative relationship with many factors, including body mass index, waist circumference, blood pressure, fasting blood glucose, and liver enzyme levels. When the LF/TF ratio and indices of hepatic steatosis were stratified by quartiles, the LF/TF ratio showed a negative correlation with the scoring systems that were used. The LF/TF ratio showed better accuracy in predicting NAFLD than total fat mass or leg fat mass alone. After adjusting for various traditional and lifestyle factors, a low LF/TF ratio remained a risk factor for NAFLD. Among NAFLD subjects, the LF/TF ratio showed a negative relationship with hepatic fibrosis.
Conclusion: A lower LF/TF ratio was markedly associated with a higher risk of hepatic steatosis and advanced hepatic fibrosis using various predictive models in a Korean population. Therefore, the LF/TF ratio could be a useful anthropometric parameter to predict NAFLD or advanced hepatic fibrosis.

Background: Farnesoid X receptor (FXR), a bile acid-activated nuclear receptor, is a potent regulator of glucose and lipid metabolism as well as of bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD), but its mechanism remains unclear. In this study, we investigated the role of FXR in atherosclerosis and NAFLD and the effect of peroxisome proliferator-activated receptor (PPAR) agonists in mouse models with FXR deficiency.
Methods: En face lipid accumulation analysis, liver histology, serum levels of glucose and lipids, and mRNA expression of genes related to lipid metabolism were compared between apolipoprotein E (ApoE)-/- and ApoE-/-FXR-/- mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice.
Results: Compared with ApoE-/- mice, ApoE-/-FXR-/- mice showed more severe atherosclerosis, hepatic steatosis, and higher levels of serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, accompanied by increased mRNA expression of FAS, ApoC2, TNFα, IL-6 (liver), ATGL, TGH, HSL, and MGL (adipocytes), and decreased mRNA expressions of CPT2 (liver) and Tfam (skeletal muscle). Treatment with a PPARα agonist, but not with a PPARγ agonist, partly reversed atherosclerosis and hepatic steatosis, and decreased plasma triglyceride levels in the ApoE-/-FXR-/- mice, in association with increased mRNA expression of CD36 and FATP and decreased expression of ApoC2 and ApoC3 (liver).
Conclusion: Loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which could be reversed by a PPARα agonist through induction of fatty acid uptake, β-oxidation, and triglyceride hydrolysis.