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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• Psychotic Disorders and the Risk of Type 2 Diabetes Mellitus, Atherosclerotic Cardiovascular Diseases, and All-Cause Mortality: A Population-Based Matched Cohort Study
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• Risk of hematologic malignant neoplasms from head CT radiation in children and adolescents presenting with minor head trauma: a nationwide population-based cohort study
  Seungjae Lee, Hae Young Kim, Kyung Hee Lee, Jungheum Cho, Choonsik Lee, Kwang Pyo Kim, Jinhee Hwang, Ji Hoon Park
  European Radiology.2024; 34(9): 5934.     CrossRef
• Risk of Depression according to Cumulative Exposure to a Low-Household Income Status in Individuals with Type 2 Diabetes Mellitus: A Nationwide Population- Based Study
  So Hee Park, You-Bin Lee, Kyu-na Lee, Bongsung Kim, So Hyun Cho, So Yoon Kwon, Jiyun Park, Gyuri Kim, Sang-Man Jin, Kyu Yeon Hur, Kyungdo Han, Jae Hyeon Kim
  Diabetes & Metabolism Journal.2024; 48(2): 290.     CrossRef
• The associations of herpes simplex virus and varicella zoster virus infection with dementia: a nationwide retrospective cohort study
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  Alzheimer's Research & Therapy.2024;[Epub]     CrossRef
• Mid- and long-term risk of atrial fibrillation among breast cancer surgery survivors
  Yong-Moon Mark Park, Wonyoung Jung, Yohwan Yeo, Sang Hyun Park, Michael G. Fradley, Sindhu J. Malapati, Tushar Tarun, Vinay Raj, Hong Seok Lee, Tasneem Z. Naqvi, Ronda S. Henry-Tillman, Jawahar L. Mehta, Mario Schootman, Benjamin C. Amick, Kyungdo Han, Do
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• Metabolic dysfunction-associated steatotic liver disease and risk of esophageal cancer in patients with diabetes mellitus: a nationwide cohort study
  Yeong Jeong Jeon, Kyungdo Han, Seung Woo Lee, Ji Eun Lee, Junhee Park, In Young Cho, Jong Ho Cho, Dong Wook Shin
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• Changes in physical activity and diabetes risk after cancer diagnosis: a nationwide cohort study
  Wonyoung Jung, In Young Cho, Jinhyung Jung, Mi Hee Cho, Hye Yeon Koo, Yong-Moon Mark Park, Jong-Ha Baek, Kyungdo Han, Dong Wook Shin
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• Income variability and incident cardiovascular disease in diabetes: a population-based cohort study
  Yong-Moon Mark Park, Jong-Ha Baek, Hong Seok Lee, Tali Elfassy, Clare C Brown, Mario Schootman, Marie-Rachelle Narcisse, Seung-Hyun Ko, Pearl A McElfish, Michael R Thomsen, Benjamin C Amick, Seong-Su Lee, Kyungdo Han
  European Heart Journal.2024; 45(21): 1920.     CrossRef
• Association between physical activity changes and risk of incident ischemic stroke following cancer diagnosis: A nationwide retrospective cohort study
  Wonyoung Jung, In Young Cho, Jinhyung Jung, Mi Hee Cho, Hye Yeon Koo, Yong‐Moon Mark Park, Be‐Long Cho, Hyuktae Kwon, Jin Ho Park, Kyungdo Han, Dong Wook Shin
  Cancer.2024; 130(16): 2873.     CrossRef
• Income dynamics and risk of colorectal cancer in individuals with type 2 diabetes: a nationwide population-based cohort study
  Yong-Moon Mark Park, Benjamin C. Amick III, Pearl A. McElfish, Clare C. Brown, Mario Schootman, Marie-Rachelle Narcisse, Seong-Su Lee, Yoon Jin Choi, Kyungdo Han
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• Risk Factors for Abdominal Aortic Aneurysm in Patients With Diabetes
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• Association between gastrectomy and the risk of type 2 diabetes in gastric cancer survivors: A nationwide cohort study
  Gyuri Kim, Kyung-do Han, So Hyun Cho, Rosa Oh, You-Bin Lee, Sang-Man Jin, Kyu Yeon Hur, Jae Hyeon Kim
  Diabetes & Metabolism.2024; 50(5): 101569.     CrossRef
• Efficacy of acupuncture on cardiovascular complications in patients with diabetes mellitus in Korea: A nationwide retrospective cohort
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  Journal of Integrative Medicine.2023; 21(2): 176.     CrossRef
• Risk of various cancers in adults with abdominal aortic aneurysms
  Hyung-jin Cho, Ju-hwan Yoo, Mi-hyeong Kim, Kyung-jai Ko, Kang-woong Jun, Kyung-do Han, Jeong-kye Hwang
  Journal of Vascular Surgery.2023; 77(1): 80.     CrossRef
• Threshold dose–response association between smoking pack-years and the risk of gallbladder cancer: A nationwide cohort study
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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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  Diabetes Care.2023; 46(1): 92.     CrossRef
• Association Between Glycemic Status and the Risk of Kidney Cancer in Men and Women: A Nationwide Cohort Study
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  Diabetes Care.2023; 46(1): 38.     CrossRef
• 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
  Wonjae Lee, Jeehoon Kang, Jun‐Bean Park, Won‐Woo Seo, Seung‐Yeon Lee, Woo‐Hyun Lim, Ki‐Hyun Jeon, In‐Chang Hwang, Hack‐Lyoung Kim
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• Risk of Dementia in Newly Diagnosed Glaucoma
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  Ophthalmology.2023; 130(7): 684.     CrossRef
• 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
  Jin Myung Park, Namyoung Park, Sang Hyub Lee, Kyung Do Han, Chang Don Kang, Jae Min Lee, Woo Hyun Paik, Ji Kon Ryu, Yong-Tae Kim
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• Blood pressure and dementia risk by physical frailty in the elderly: a nationwide cohort study
  Mi Hee Cho, Kyungdo Han, Seungwoo Lee, Su-Min Jeong, Jung Eun Yoo, SangYun Kim, Jinkook Lee, Sohyun Chun, Dong Wook Shin
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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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• 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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  Healthcare.2023; 11(24): 3171.     CrossRef
• 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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  Hypertension.2022; 79(1): 218.     CrossRef
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  Gastroenterology.2022; 162(2): 509.     CrossRef
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  European Heart Journal.2022; 43(15): 1491.     CrossRef
• Blood Pressure Variability and the Risk of Fracture: A Nationwide Cohort Study
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  The Journal of Clinical Endocrinology & Metabolism.2022; 107(4): e1488.     CrossRef
• 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
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  Eugene Han, Kyung-do Han, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Seung-Hyun Ko, Yong-ho Lee
  The Journal of Clinical Endocrinology & Metabolism.2022; 107(5): e1976.     CrossRef
• 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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  Biomedicines.2022; 10(2): 303.     CrossRef
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  Yoonjeong Choi, Eun Young Kim, Jiyu Sun, Han-Kyoul Kim, Ye Seol Lee, Byung-Mo Oh, Hye Yoon Park, Ja-Ho Leigh
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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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  Journal of Clinical Medicine.2022; 11(4): 1077.     CrossRef
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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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  The Korean Journal of Internal Medicine.2022; 37(3): 639.     CrossRef
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  Journal of Lipid and Atherosclerosis.2022; 11(2): 103.     CrossRef
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  Joo-Hyun Park, Jung Yong Hong, Kyungdo Han, Young Suk Park, Joon Oh Park
  Journal of Clinical Oncology.2022; 40(31): 3623.     CrossRef
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  Soo‐Yoon Sung, Hyun Ho Choi, Sukil Kim, Bo Ram Park, Young Ki Kim, Hyung‐Keun Kim, Young‐Seok Cho, Sang Woo Kim, Sung Soo Kim, Hiun‐Suk Chae
  Journal of Gastroenterology and Hepatology.2022; 37(10): 1991.     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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  Diabetes & Metabolism Journal.2022; 46(4): 567.     CrossRef
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  Mee Kyoung Kim, Kyungdo Han, Seung-Hwan Lee
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  Tae Hwa Hong, Hyung Seok Lee, Nam-Eun Kim, Kyu Jin Lee, Yong Kyun Kim, Jung Nam An, Joo-Hee Kim, Hyung Won Kim, Sunghoon Park
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  You-Bin Lee, Minji Koo, Eunjin Noh, Soon Young Hwang, Jung A Kim, Eun Roh, So-hyeon Hong, Kyung Mook Choi, Sei Hyun Baik, Geum Joon Cho, Hye Jin Yoo
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• Severe hypoglycemia and risk of hospitalization for heart failure in adults with diabetes treated with oral medications with or without insulin: A population-based study
  You-Bin Lee, Yoon-Jong Bae, Hoseob Kim, Jiyun Park, So Yoon Kwon, So Hee Park, Gyuri Kim, Kyu Yeon Hur, Jae Hyeon Kim, Sang-Man Jin
  Diabetes Research and Clinical Practice.2022; 192: 110083.     CrossRef
• 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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