Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping

Zhipeng Liu, Yang Zhang, Sarah Graham, Xiaokun Wang, Defeng Cai, Menghao Huang, Roger Pique-Regi, Xiaocheng Charlie Dong, Y. Eugene Chen, Cristen Willer, Wanqing Liu

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Background & 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.

Original languageEnglish (US)
Pages (from-to)263-276
Number of pages14
JournalJournal of Hepatology
Issue number2
StatePublished - Aug 2020


  • Mendelian randomization
  • Non-alcoholic fatty liver disease
  • Obesity
  • PNPLA3
  • Type 2 diabetes

ASJC Scopus subject areas

  • Hepatology

Fingerprint Dive into the research topics of 'Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping'. Together they form a unique fingerprint.

Cite this