Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in adults and children worldwide. NAFLD has become a severe health issue and it can progress towards a more severe form of the disease, the non-alcoholic steatohepatitis (NASH). A combination of environmental factors, host genetics, and gut microbiota leads to excessive accumulation of lipids in the liver (steatosis), which may result in lipotoxicity and trigger hepatocyte cell death, liver inflammation, fibrosis, and pathological angiogenesis. NASH can further progress towards liver cirrhosis and cancer. Over the last few years, cell-derived extracellular vesicles (EVs) have been identified as effective cell-to-cell messengers that transfer several bioactive molecules in target cells, modulating the pathogenesis and progression of NASH. In this review, we focused on recently highlighted aspects of molecular pathogenesis of NASH, mediated by EVs via their bioactive components. The studies included in this review summarize the state of art regarding the role of EVs during the progression of NASH and bring novel insight about the potential use of EVs for diagnosis and therapeutic strategies for patients with this disease.

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Brown fat is a specialized fat depot that can increase energy expenditure and produce heat. After the recent discovery of the presence of active brown fat in human adults and novel transcription factors controlling brown adipocyte differentiation, the field of the study of brown fat has gained great interest and is rapidly growing. Brown fat expansion and/or activation results in increased energy expenditure and a negative energy balance in mice and limits weight gain. Brown fat is also able to utilize blood glucose and lipid and results in improved glucose metabolism and blood lipid independent of weight loss. Prolonged cold exposure and beta adrenergic agonists can induce browning of white adipose tissue. The inducible brown adipocyte, beige adipocyte evolving by thermogenic activation of white adipose tissue have different origin and molecular signature from classical brown adipocytes but share the characteristics of high mitochondria content, UCP1 expression and thermogenic capacity when activated. Increasing browning may also be an efficient way to increase whole brown fat activity. Recent human studies have shown possibilities that findings in mice can be reproduced in human, making brown fat a good candidate organ to treat obesity and its related disorders.

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Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on energy metabolism and insulin sensitivity. Besides its antiobese and antidiabetic activity, FGF21 also possesses the protective effects against atherosclerosis. Circulating levels of FGF21 are elevated in patients with atherosclerosis, macrovascular and microvascular complications of diabetes, possibly due to a compensatory upregulation. In apolipoprotein E-deficient mice, formation of atherosclerotic plaques is exacerbated by genetic depletion of FGF21, but is attenuated upon replenishment with recombinant FGF21. However, the blood vessel is not the direct target of FGF21, and the antiatherosclerotic activity of FGF21 is attributed to its actions in adipose tissues and liver. In adipocytes, FGF21 promotes secretion of adiponectin, which in turn acts directly on blood vessels to reduce endothelial dysfunction, inhibit proliferation of smooth muscle cells and block conversion of macrophages to foam cells. Furthermore, FGF21 suppresses cholesterol biosynthesis and attenuates hypercholesterolemia by inhibiting the transcription factor sterol regulatory element-binding protein-2 in hepatocytes. The effects of FGF21 on elevation of adiponectin and reduction of hypercholesterolemia are also observed in a phase-1b clinical trial in patients with obesity and diabetes. Therefore, FGF21 exerts its protection against atherosclerosis by fine-tuning the interorgan crosstalk between liver, brain, adipose tissue, and blood vessels.

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In 2014, the National Health Insurance Service (NHIS) signed a memorandum of understanding with the Korean Diabetes Association to provide limited open access to its databases for investigating the past and current status of diabetes and its management. NHIS databases include the entire Korean population; therefore, it can be used as a population-based nationwide study for various diseases, including diabetes and its complications. This report presents how we established the analytic system of nation-wide population-based studies using the NHIS database as follows: the selection of database study population and its distribution and operational definition of diabetes and patients of currently ongoing collaboration projects.

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  European Journal of Cancer.2023; 180: 99.     CrossRef
• Sustained Low Income, Income Changes, and Risk of All-Cause Mortality in Individuals With Type 2 Diabetes: A Nationwide Population-Based Cohort Study
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• Association Between Glycemic Status and the Risk of Kidney Cancer in Men and Women: A Nationwide Cohort Study
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• Increased end-stage renal disease risk in age-related macular degeneration: a nationwide cohort study with 10-year follow-up
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• Long‐term mortality and cardiovascular events of seven angiotensin receptor blockers in hypertensive patients: Analysis of a national real‐world database: A retrospective cohort study
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• Risk of Dementia in Newly Diagnosed Glaucoma
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• Associations of reproductive factors with incidence of myocardial infarction and ischemic stroke in postmenopausal women: a cohort study
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• Association of general and central obesity, and their changes with risk of knee osteoarthritis: a nationwide population-based cohort study
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• Comparison of Operational Definition of Type 2 Diabetes Mellitus Based on Data from Korean National Health Insurance Service and Korea National Health and Nutrition Examination Survey
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• A population-based cohort study on risk factors for acute pancreatitis: A comparison by age group
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• Blood pressure and dementia risk by physical frailty in the elderly: a nationwide cohort study
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• Cumulative exposure to metabolic syndrome in a national population-based cohort of young adults and sex-specific risk for type 2 diabetes
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• Age‐Related Macular Degeneration With Visual Disability Is Associated With Cardiovascular Disease Risk in the Korean Nationwide Cohort
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• Association of Metabolic Syndrome Components and Nutritional Status with Kidney Cancer in Young Adult Population: A Nationwide Population-Based Cohort Study in Korea
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• Nationwide trends in the prevalence and incidence of depressive disorders and their correlates among adults with disabilities in Korea from 2006 to 2017
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  International Journal of Social Psychiatry.2023; 69(7): 1670.     CrossRef
• Association between glycemic status and the risk of acute pancreatitis: a nationwide population-based study
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• Association between fatty liver index and risk of end-stage renal disease stratified by kidney function in patients with type 2 diabetes: A nationwide population-based study
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  Diabetes & Metabolism.2023; 49(4): 101454.     CrossRef
• Incidence and adverse clinical events of primary sclerosing cholangitis with ulcerative colitis
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• Risk of developing chronic kidney disease in young-onset Type 2 diabetes in Korea
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• A cohort study found a high risk of end-stage kidney disease associated with acromegaly
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• Higher metabolic variability increases the risk of depressive disorder in type 2 diabetes mellitus: a longitudinal nationwide cohort study
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• Association of Sustained Low or High Income and Income Changes With Risk of Incident Type 2 Diabetes Among Individuals Aged 30 to 64 Years
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• Developing Operational Definitions Related toHelicobacter pyloriEradication Therapy
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• The impact of diabetes status on total and site-specific cancer risk in the elderly population: A nationwide cohort study
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• Impact of Concomitant Use of Proton Pump Inhibitors and Clopidogrel on Recurrent Stroke and Myocardial Infarction
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  Pharmaceuticals.2023; 16(9): 1213.     CrossRef
• Prevalence, Treatment Status, and Comorbidities of Hyperthyroidism in Korea from 2003 to 2018: A Nationwide Population Study
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• Low Household Income Status and Death from Pneumonia in People with Type 2 Diabetes Mellitus: A Nationwide Study
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• Risk of depression in patients with acromegaly in Korea (2006-2016): a nationwide population-based study
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  European Journal of Endocrinology.2023; 189(3): 363.     CrossRef
• Real-world survival after colorectal surgery for malignancy in Korean patients with chronic kidney disease: an analysis of Korean healthcare big data, 2002–2019
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• Association between Smoking Cessation and the Risk of Cholangiocarcinoma and Ampulla of Vater Cancer: A Nationwide Cohort Study
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• Changes in smoking, alcohol consumption, and the risk of Parkinson’s disease
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• Association between Dental Diseases and Oral Hygiene Care and the Risk of Dementia: A Retrospective Cohort Study
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  Journal of the American Medical Directors Association.2023; 24(12): 1924.     CrossRef
• The Effect of Cataract Surgery on the Risk of Dementia: A Nationwide Cohort Study
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• The Impact of Neighborhood Deprivation on the Survival Rates of Patients with Cancer in Korea
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• Declined incidence of patients treated for vision-threatening diabetic retinopathy in South Korea: a 12-year nationwide population-based study
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• Female reproductive factors and risk of joint replacement arthroplasty of the knee and hip due to osteoarthritis in postmenopausal women: a nationwide cohort study of 1.13 million women
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• Blood Pressure Levels and Risks of Dementia: a Nationwide Study of 4.5 Million People
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• Changes in Metabolic Syndrome Status are Associated With Altered Risk of Pancreatic Cancer: A Nationwide Cohort Study
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• Acromegaly and cardiovascular outcomes: a cohort study
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• Blood Pressure Variability and the Risk of Fracture: A Nationwide Cohort Study
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• Cost-effectiveness analysis of intensive blood pressure control in Korea
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• Associations of variability in body weight and glucose levels with the risk of hip fracture in people with diabetes
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  Metabolism.2022; 129: 155135.     CrossRef
• Severe Hypoglycemia Increases Dementia Risk and Related Mortality: A Nationwide, Population-based Cohort Study
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• Association between alcohol consumption and pancreatic cancer risk differs by glycaemic status: A nationwide cohort study
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  European Journal of Cancer.2022; 163: 119.     CrossRef
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• Female Reproductive Factors and the Risk of Bronchiectasis: A Nationwide Population-Based Longitudinal Study
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• Blood pressure and mortality after percutaneous coronary intervention: a population-based cohort study
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• Impaired Lung Function and Lung Cancer Incidence: A Nationwide Population-Based Cohort Study
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• Hip Fracture Risk According to Diabetic Kidney Disease Phenotype in a Korean Population
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• Medical Utilization and Costs in Preterm Infants in the First 6 Years of Life After Discharge From Neonatal Intensive Care Unit: A Nationwide Population-Based Study in Korea
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  Journal of Clinical Oncology.2022; 40(31): 3623.     CrossRef
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  International Journal of Environmental Research and Public Health.2022; 19(14): 8615.     CrossRef
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• Comparative Effects of Sodium-Glucose Cotransporter 2 Inhibitor and Thiazolidinedione Treatment on Risk of Stroke among Patients with Type 2 Diabetes Mellitus
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• Real-World Prescription Patterns and Barriers Related to the Use of Sodium-Glucose Cotransporter 2 Inhibitors among Korean Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease
  Jong Ha Baek, Ye Seul Yang, Seung-Hyun Ko, Kyung Do Han, Jae Hyeon Kim, Min Kyong Moon, Jong Suk Park, Byung-Wan Lee, Tae Jung Oh, Suk Chon, Jong Han Choi, Kyu Yeon Hur
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  Jeonggeun Moon, Pyung Chun Oh, Kyounghoon Lee, Ho-Jun Jang, Tae-Hoon Kim, Sang-Don Park, Sung Woo Kwon, Min Gyu Kong, Jon Suh, Woong Chol Kang
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• Fasting Glucose Variability and the Risk of Dementia in Individuals with Diabetes: A Nationwide Cohort Study
  Da Young Lee, Jaeyoung Kim, Sanghyun Park, So Young Park, Ji Hee Yu, Ji A Seo, Nam Hoon Kim, Hye Jin Yoo, Sin Gon Kim, Kyung Mook Choi, Sei Hyun Baik, Kyungdo Han, Nan Hee Kim
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  Dae Young Cheon, Kyungdo Han, Ye Seul Yang, Yerim Kim, Sang-Hwa Lee, Chulho Kim, Jong-Hee Sohn, Mi Sun Oh, Byung-Chul Lee, Minwoo Lee, Kyung-Ho Yu
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  SSRN Electronic Journal .2022;[Epub]     CrossRef
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• Tooth loss and risk of end‐stage renal disease: A nationwide cohort study
  Kyungdo Han, Jun‐Beom Park
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  J.M. Bae, Y.‐S. Kim, E.H. Choo, M.‐Y. Kim, J.Y. Lee, H.‐O. Kim, Y.M. Park
  Journal of the European Academy of Dermatology and Venereology.2021; 35(1): 222.     CrossRef
• The risk of hip fractures in individuals over 50 years old with prediabetes and type 2 diabetes – A longitudinal nationwide population-based study
  Ho Youn Park, Kyoungdo Han, Youngwoo Kim, Yoon Hwan Kim, Yoo Joon Sur
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• Association of Female Reproductive Factors With Incidence of Fracture Among Postmenopausal Women in Korea
  Jung Eun Yoo, Dong Wook Shin, Kyungdo Han, Dahye Kim, Ji Won Yoon, Dong-Yun Lee
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  Seong-Su Moon, Chong Hwa Kim, Seon Mee Kang, Eun Sook Kim, Tae Jung Oh, Jae-Seung Yun, Ho Chan Cho, Dae Jung Kim, Tae Sun Park
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• High-Density Lipoprotein Cholesterol and the Risk of Myocardial Infarction, Stroke, and Cause-Specific Mortality: a Nationwide Cohort Study in Korea
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• Estimated Incidence and Projections of Treatment Cost for Vision-threatening Diabetic Retinopathy in Korea
  Hyo Jin Seong, Jiwon Kim, Sunok Song, Kangju Son, Sungyong Park, Eun Jee Chung
  Journal of the Korean Ophthalmological Society.2021; 62(1): 55.     CrossRef
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