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Item Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping(Elsevier, 2020-08) Liu, Zhipeng; Zhang, Yang; Graham, Sarah; Wang, Xiaokun; Cai, Defeng; Huang, Menghao; Pique-Regi, Roger; Dong, Xiaocheng Charlie; Chen, Y. Eugene; Willer, Cristen; Liu, Wanqing; Biochemistry and Molecular Biology, School of MedicineBackground & aims: Non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D) and obesity are epidemiologically correlated with each other but the causal inter-relationships between them remain incompletely understood. We aimed to explore the causal relationships between the 3 diseases. Methods: Using both UK Biobank and publicly available genome-wide association study data, we performed a 2-sample bidirectional Mendelian randomization analysis to test the causal inter-relationships between NAFLD, T2D, and obesity. Transgenic mice expressing the human PNPLA3-I148M isoforms (TghPNPLA3-I148M) were used as an example to validate causal effects and explore underlying mechanisms. Results: Genetically driven NAFLD significantly increased the risk of T2D and central obesity but not insulin resistance or generalized obesity, while genetically driven T2D, body mass index and WHRadjBMI causally increased NAFLD risk. The animal study focusing on PNPLA3 corroborated these causal effects: compared to the TghPNPLA3-I148I controls, the TghPNPLA3-I148M mice developed glucose intolerance and increased visceral fat, but maintained normal insulin sensitivity, reduced body weight, and decreased circulating total cholesterol. Mechanistically, the TghPNPLA3-I148M mice demonstrated decreased pancreatic insulin but increased glucagon secretion, which was associated with increased pancreatic inflammation. In addition, transcription of hepatic cholesterol biosynthesis pathway genes was significantly suppressed, while transcription of thermogenic pathway genes was activated in subcutaneous and brown adipose tissues but not in visceral fat in TghPNPLA3-I148M mice. Conclusions: Our study suggests that lifelong, genetically driven NAFLD causally promotes T2D with a late-onset type 1-like diabetic subphenotype and central obesity; while genetically driven T2D, obesity, and central obesity all causally increase the risk of NAFLD. This causal relationship revealed new insights into how nature and nurture drive these diseases, providing novel hypotheses for disease subphenotyping. Lay summary: Non-alcoholic fatty liver disease, type 2 diabetes and obesity are epidemiologically correlated with each other, but their causal relationships were incompletely understood. Herein, we identified causal relationships between these conditions, which suggest that each of these closely related diseases should be further stratified into subtypes. This is important for accurate diagnosis, prevention and treatment of these diseases.Item Clinical Characteristics and Outcomes of Mild to Moderate Alcoholic Hepatitis(Wiley, 2019) Samala, Niharika; Gawrieh, Samer; Tang, Qing; Lourens, Spencer G.; Shah, Vijay H.; Sanyal, Arun J.; Liangpunsakul, Suthat; Chalasani, Naga; Medicine, School of MedicineIntroduction & Aim Much is known about alcoholic hepatitis (AH) that is severe enough to require hospitalisation. The characteristics of individuals with alcoholic hepatitis presenting with mild to moderate severity are not well understood. In this study, we investigated the risk factors, characteristics and outcomes of mild to moderate AH (M‐AH). Methods A total of 255 individuals with AH enrolled into a multicenter, prospective, observational study between 12/2014 and 4/2018 was included. Participants were seen at enrollment, 6 and 12 months. M‐AH was defined as MELD ≤20 at presentation, whereas severe AH as MELD ≥21. Results In total, 100 individuals had M‐AH, whereas 155 had severe AH. Individuals with M‐AH were older (49 vs 44 years, P = 0.01), had lower BMI (27 vs 31 kg/m2, P = 0.0007) and more likely to be male (68% vs 55%, P = 0.046) compared to the severe AH group. A higher proportion in the M‐AH group consumed coffee in the last 5 years compared to the severe AH group (29% vs 18%, P = 0.03), and fewer had PNPLA3 risk allele G (P = 0.019) compared to the severe AH group. Average drinks per drinking day (12.9 vs 10.7, P = 0.13) and total number of drinks in last 30‐day period (331 vs 280, P = 0.14) were not different between two groups. Compared to severe AH, patients with M‐AH had significantly lower mortality at 30 days (2% vs 13.6%), 90 days (3% vs 22.6%) and 12 months (10.4% vs 31.4%) (P < 0.001 for all). Conclusions Individuals with M‐AH were older, less obese, drank coffee more often and carried more favourable PNPLA3 genotype compared to severe AH, despite similar alcohol consumption. M‐AH had substantial mortality with one in ten dying by 12 months.Item PNPLA3—A Potential Therapeutic Target for Personalized Treatment of Chronic Liver Disease(Frontiers Media, 2019-12-17) Dong, Xiaocheng Charlie; Biochemistry and Molecular Biology, School of MedicinePatatin-like phospholipase domain-containing protein 3 (PNPLA3) is a lipid droplet-associated protein that has been shown to have hydrolase activity toward triglycerides and retinyl esters. The first evidence of PNPLA3 being associated with fatty liver disease was revealed by a genome-wide association study (GWAS) of Hispanic, African American, and European American individuals in the Dallas Heart Study back in 2008. Since then, numerous GWAS reports have shown that PNPLA3 rs738409[G] (148M) variant is associated with hepatic triglyceride accumulation (steatosis), inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma regardless of etiologies including alcohol- or obesity-related and others. The frequency of PNPLA3(148M) variant ranges from 17% in African Americans, 23% in European Americans, to 49% in Hispanics in the Dallas Heart Study. Due to high prevalence of obesity and alcohol consumption in modern societies, the PNPLA3(148M) gene variant and environment interaction poses a serious concern for public health, especially chronic liver diseases including alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Therefore, PNPLA3(148M) variant is a potential therapeutic target for chronic liver disease in the rs738409 allele carriers. Currently, there is no approved drug specifically targeting the PNPLA3(148M) variant yet. With additional mechanistic studies, novel therapeutic strategies are expected to be developed for the treatment of the PNPLA3(148M) variant-associated chronic liver diseases in the near future.Item Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans(Impact Journals, 2016-10-13) Liu, Wanqing; Anstee, Quentin M.; Wang, Xiaoliang; Gawrieh, Samer; Gamazon, Eric R.; Athinarayanan, Shaminie; Liu, Yang-Lin; Darlay, Rebecca; Cordell, Heather J.; Daly, Ann K.; Day, Chris P.; Chalasani, Naga; Department of Medicine, IU School of MedicineThe increased expression of PNPLA3148M leads to hepatosteatosis in mice. This study aims to investigate the genetic control of hepatic PNPLA3 transcription and to explore its impact on NAFLD risk in humans. Through a locus-wide expression quantitative trait loci (eQTL) mapping in two human liver sample sets, a PNPLA3 intronic SNP, rs139051 A>G was identified as a significant eQTL (p = 6.6×10-8) influencing PNPLA3 transcription, with the A allele significantly associated with increased PNPLA3 mRNA. An electrophoresis mobility shift assay further demonstrated that the A allele has enhanced affinity to nuclear proteins than the G allele. The impact of this eQTL on NAFLD risk was further tested in three independent populations. We found that rs139051 did not independently affect the NAFLD risk, whilst rs738409 did not significantly modulate PNPLA3 transcription but was associated with NAFLD risk. The A-G haplotype associated with higher transcription of the disease-risk rs738409 G allele conferred similar risk for NAFLD compared to the G-G haplotype that possesses a lower transcription level. Our study suggests that the pathogenic role of PNPLA3148M in NAFLD is independent of the gene transcription in humans, which may be attributed to the high endogenous transcription level of PNPLA3 gene in human livers.