Background
Non‐alcoholic fatty liver disease (NAFLD) and sarcopenia share insulin resistance as a common pathophysiology and have overlapping clinical manifestation of metabolic derangement; hence, ...it is difficult to differentiate the independent effect of sarcopenia on the development of NAFLD from concomitant metabolic disorders. Using a community‐based prospective cohort study, the contributions of low muscle mass and genetic risk factors to the development of NAFLD and NAFLD‐related hepatic fibrosis were investigated in the Korean population.
Methods
This prospective community‐based cohort study included 40–70‐year‐old adults, followed up biennially from 2001–2002 to 2017–2018. NAFLD was defined as a hepatic steatosis index of ≥36, and hepatic fibrosis was defined based on the fibrosis‐4 index. Sex‐specific quartiles of body mass index (BMI)‐adjusted muscle mass were calculated (muscle mass/BMI), and low muscle mass was defined as the lowest quartile (Q1). Cox proportional hazard models for incident NAFLD or hepatic fibrosis incorporating age, sex, BMI of ≥25 kg/m2, metabolic syndrome and PNPLA3 and TM6SF2 risk alleles were used to assess the independent determinants for incident NAFLD and hepatic fibrosis among individuals with NAFLD at baseline.
Results
Among the 4038 participants without NAFLD at baseline (mean age, 51.5 ± 8.8 years), 920 (22.8%) developed NAFLD during the 12‐year follow‐up period. As muscle mass decreased, the risk of NAFLD increased even after adjustment for age, sex, obesity, metabolic syndrome and PNPLA3 and TM6SF2 risk alleles hazard ratio (HR) per quartile, 1.18, 95% confidence interval (CI), 1.11–1.27, P < 0.001. TM6SF2 also affected the risk of NAFLD development HR 1.19, (95% CI, 1.00–1.40), P = 0.044.
Of the 1176 patients with NAFLD but without hepatic fibrosis at baseline, the incident of hepatic fibrosis was found in 51.8%, 44.7%, 42.6% and 41.0% in Q1, Q2, Q3 and Q4 of BMI‐adjusted muscle mass, respectively, during the follow‐up period (P for trend = 0.006). However, this trend lost its statistical significance when adjusted for confounders. The PNPLA3 risk variant, but not the TM6SF2 genotype, was an independent risk factor for developing hepatic fibrosis among patients with NAFLD (HR 1.17, 95% CI 1.04–1.32, P = 0.010).
Conclusions
Both lower muscle mass index and genetic risk variants are important contributors to the development of NAFLD. In patients already diagnosed with NAFLD, however, PNPLA3 confers a greater risk for hepatic fibrosis progression than lower muscle mass.
Adiponectin plays a key role in the regulation of the whole-body energy homeostasis by modulating glucose and lipid metabolism. Although obesity-induced reduction of adiponectin expression is ...primarily ascribed to a transcriptional regulation failure, the underlying mechanisms are largely undefined. Here we show that DNA hypermethylation of a particular region of the adiponectin promoter suppresses adiponectin expression through epigenetic control and, in turn, exacerbates metabolic diseases in obesity. Obesity-induced, pro-inflammatory cytokines promote DNMT1 expression and its enzymatic activity. Activated DNMT1 selectively methylates and stimulates compact chromatin structure in the adiponectin promoter, impeding adiponectin expression. Suppressing DNMT1 activity with a DNMT inhibitor resulted in the amelioration of obesity-induced glucose intolerance and insulin resistance in an adiponectin-dependent manner. These findings suggest a critical role of adiponectin gene epigenetic control by DNMT1 in governing energy homeostasis, implying that modulating DNMT1 activity represents a new strategy for the treatment of obesity-related diseases.
OBJECTIVE:--The dysregulation of adipokines is closely associated with the pathogenesis of insulin resistance and type 2 diabetes. Retinol-binding protein-4 (RBP4), a new adipokine, was recently ...reported to provide a link between obesity and insulin resistance. Here, we examined the relation between plasma RBP4 concentrations and various metabolic parameters in humans. RESEARCH DESIGN AND METHODS--An enzyme-linked immunosorbent assay was developed to measure human RBP4 plasma concentrations, which were then compared with various parameters related to insulin resistance in subjects with normal glucose tolerance (NGT; n = 57), impaired glucose tolerance (IGT; n = 48), and type 2 diabetes (n = 49). RESULTS:--Plasma RBP4 concentrations were higher in the IGT and type 2 diabetic groups than in the NGT group (median 18.9 range 11.2-45.8, 20.9 9.9-48.5, and 18.1 μg/ml 9.3-30.5, respectively). However, no difference was found between plasma RBP4 concentrations in the IGT and type 2 diabetic groups. Plasma RBP4 concentrations were found to be associated with sex, waist circumference, fasting plasma glucose, and insulin resistance. Of these, sex and fasting plasma glucose levels were found to be independent determinants of plasma RBP4 concentration. CONCLUSIONS:--Plasma RBP4 concentrations were found to be elevated in subjects with IGT or type 2 diabetes and to be related to various clinical parameters known to be associated with insulin resistance.
Joint modelling of genetic and environmental risk factors can provide important information to predict the risk of type 2 diabetes (T2D). Therefore, to predict the genetic risk of T2D, we constructed ...a polygenic risk score (PRS) using genotype data of one Korean cohort, KARE (745 cases and 2549 controls), and the genome-wide association study summary statistics of Biobank Japan. We evaluated the performance of PRS in an independent Korean cohort, HEXA (5684 cases and 35,703 controls). Individuals with T2D had a significantly higher mean PRS than controls (0.492 vs. - 0.078, p
). PRS predicted the risk of T2D with an AUC of 0.658 (95% CI 0.651-0.666). We also evaluated interaction between PRS and waist circumference (WC) in the HEXA cohort. PRS exhibited a significant sub-multiplicative interaction with WC (OR
0.991, 95% CI 0.987-0.995, p
= 4.93 × 10
) in T2D. The effect of WC on T2D decreased as PRS increased. The sex-specific analyses produced similar interaction results, revealing a decreased WC effect on T2D as the PRS increased. In conclusion, the risk of WC for T2D may differ depending on PRS and those with a high PRS might develop T2D with a lower WC threshold. Our findings are expected to improve risk prediction for T2D and facilitate the identification of individuals at an increased risk of T2D.
The PNPLA3 rs738409 G allele increases the risk of not only nonalcoholic fatty liver disease (NAFLD) but also nonalcoholic steatohepatitis (NASH) or fibrosis.
It also affects the prognosis of ...patients with NAFLD in specific conditions. After liver transplantation, patients with NAFLD carrying the rs738409 GG genotype have a higher risk of graft steatosis
or development of hepatocellular carcinoma.
In addition, rs738409 modifies the effects of medical intervention: patients with NAFLD carrying the GG genotype showed a lower effect of omega-3 polyunsaturated fatty acid treatment on the reduction of liver fat;
in contrast, they were more sensitive to the beneficial effects of lifestyle modifications.
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OBJECTIVE: The number of people with metabolic syndrome is increasing worldwide, and changes in socioenvironmental factors contribute to this increase. Therefore, investigation of changes in ...metabolic syndrome and its components in South Korea, where rapid socioenvironmental changes have occurred in recent years, would be foundational in setting up an effective strategy for reducing this increasing trend. RESEARCH DESIGN AND METHODS: We compared the prevalence and pattern of metabolic syndrome among participants in the Korean National Health and Nutrition Examination Surveys for 1998, 2001, 2005, and 2007. In each survey, stratified, multistage, probability-sampling designs and weighting adjustments were conducted to represent the entire Korean population. The revised National Cholesterol Education Program criteria were used as the definition of metabolic syndrome. All biochemical parameters were measured in a central laboratory. RESULTS: A total of 6,907 (mean ± SE age 45.0 ± 0.2 years), 4,536 (45.5 ± 0.2), 5,373 (47.1 ± 0.2), and 2,890 (49.9 ± 0.3) Koreans over 20 years of age have participated in the studies in 1998, 2001, 2005, and 2007, respectively. The age-adjusted prevalence of metabolic syndrome increased significantly from 24.9% in 1998, 29.2% in 2001, and 30.4% in 2005 to 31.3% in 2007. Among the five components, the level of low HDL cholesterol increased the most, by 13.8% over the 10 years. Abdominal obesity and hypertriglyceridemia followed, with 8.7 and 4.9% increases, respectively. CONCLUSIONS: Because dyslipidemia and abdominal obesity were major factors in increasing the prevalence of metabolic syndrome in Koreans for the past 10 years, lifestyle interventions should be conducted at the national level to reduce the burden and consequences of metabolic syndrome.
Abstract
Aims
Proprotein convertase subtilisin/kexin type-9 (PCSK9), a molecular determinant of low-density lipoprotein (LDL) receptor (LDLR) fate, has emerged as a promising therapeutic target for ...atherosclerotic cardiovascular diseases. However, the precise mechanism by which PCSK9 regulates the internalization and lysosomal degradation of LDLR is unknown. Recently, we identified adenylyl cyclase-associated protein 1 (CAP1) as a receptor for human resistin whose globular C-terminus is structurally similar to the C-terminal cysteine-rich domain (CRD) of PCSK9. Herein, we investigated the role of CAP1 in PCSK9-mediated lysosomal degradation of LDLR and plasma LDL cholesterol (LDL-C) levels.
Methods and results
The direct binding between PCSK9 and CAP1 was confirmed by immunoprecipitation assay, far-western blot, biomolecular fluorescence complementation, and surface plasmon resonance assay. Fine mapping revealed that the CRD of PCSK9 binds with the Src homology 3 binding domain (SH3BD) of CAP1. Two loss-of-function polymorphisms found in human PCSK9 (S668R and G670E in CRD) were attributed to a defective interaction with CAP1. siRNA against CAP1 reduced the PCSK9-mediated degradation of LDLR in vitro. We generated CAP1 knock-out mice and found that the viable heterozygous CAP1 knock-out mice had higher protein levels of LDLR and lower LDL-C levels in the liver and plasma, respectively, than the control mice. Mechanistic analysis revealed that PCSK9-induced endocytosis and lysosomal degradation of LDLR were mediated by caveolin but not by clathrin, and they were dependent on binding between CAP1 and caveolin-1.
Conclusion
We identified CAP1 as a new binding partner of PCSK9 and a key mediator of caveolae-dependent endocytosis and lysosomal degradation of LDLR.
The relative contributions of β-cell function and insulin sensitivity in the pathogenesis of type 2 diabetes are not fully understood. We investigated the longitudinal change in β-cell function and ...insulin sensitivity in the development of diabetes and the role of genetic variants in deterioration of glucose tolerance.
We followed up 4106 participants with normal glucose tolerance (NGT) from the Korean Genome and Epidemiology Study with oral glucose tolerance tests every 2 years for 10 years. We estimated pancreatic β-cell function with the 60 min insulinogenic index (IGI60) and insulin sensitivity with the composite (Matsuda) insulin sensitivity index (ISI). We investigated the association of 66 known type 2 diabetes genetic variants with risk of prediabetes or diabetes and impaired β-cell function and insulin sensitivity.
During 10 years of follow-up, 1093 (27%) of 4106 participants developed prediabetes and 498 (12%) participants developed diabetes. Compared with participants who remained NGT, those who progressed to diabetes had a lower IGI60 (unadjusted data 5·1 μU/mmol 95% CI 0·5-56·1 vs 7·9 μU/mmol 0·5-113·8; p<0·0001) and lower ISI (unadjusted data 8·2 2·6-26·0 vs 10·0 3·2-31·6; p<0·0001) at baseline. Participants who had NGT at 10 years showed a decrease in ISI (adjusted data 10·1 9·9-10·3 vs 7·4 7·3-7·6; p<0·0001) but a compensatory increase in IGI60 (adjusted data 6·9 μU/mmol 6·5-7·2 vs 11·7 μU/mmol 11·2-12·1; p<0·0001) compared with baseline. By contrast, participants who developed diabetes showed a decrease in ISI (adjusted data 8·4 8·0-8·7 vs 3·0 2·8-3·2; p<0·0001) but no significant compensatory increase (p=0·95) in IGI60. A genetic variant near the glucokinase gene (rs4607517) was significantly associated with progression to prediabetes or diabetes (hazard ratio 1·27, 1·16-1·38; p=1·70 × 10(-7)).
Decreased β-cell function, which might be determined partly by genetic factors, and impaired β-cell compensation for progressive decline in insulin sensitivity are crucial factors in the deterioration of glucose tolerance.
South Korean Ministry of Health & Welfare.
Thyroid cancer is the most common cancer in Korea. Several susceptibility loci of differentiated thyroid cancer (DTC) were identified by previous genome-wide association studies (GWASs) in Europeans ...only. Here we conducted a GWAS and a replication study in Koreans using a total of 1,085 DTC cases and 8,884 controls, and validated these results using expression quantitative trait loci (eQTL) analysis and clinical phenotypes. The most robust associations were observed in the NRG1 gene (rs6996585, P=1.08 × 10
) and this SNP was also associated with NRG1 expression in thyroid tissues. In addition, we confirmed three previously reported loci (FOXE1, NKX2-1 and DIRC3) and identified seven novel susceptibility loci (VAV3, PCNXL2, INSR, MRSB3, FHIT, SEPT11 and SLC24A6) associated with DTC. Furthermore, we identified specific variants of DTC that have different effects according to cancer type or ethnicity. Our findings provide deeper insight into the genetic contribution to thyroid cancer in different populations.
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