Introduction: Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity but is occurring in increasing numbers in young non-obese patients and is known as "lean NAFLD", whose underlying pathophysiology is not well understood. We aimed to advance mechanistic understanding of lean NAFLD using guinea pigs fed a western diet (WD) during postnatal growing phase.
Methods: Normally in utero grown guinea pig offspring were randomly assigned to receive ad libitum a control (CD) diet or WD (high fat/high sugar + 0.25% cholesterol) from weaning to postnatal day (PND) 150 (young adulthood). In vivo computed tomography (CT, ~ PDN 120), organ weight determinations and hepatic histology analyses (150 PDN) were undertaken. Hepatic differentially expressed genes (DEGs) were identified using the GeneChip™ Guinea Pig Gene 1.1 ST Array Plate and TAC software (-22, FRD p-value<0.05). Functional analysis was carried out on DEGs using g:Profiler.
Results: CT and adipose tissue weights, revealed that male and female WD offspring were not obese. However, at PND 150, male and female WD offspring developed hepatomegaly, prominent hepatic steatosis, lobular liver inflammation and fibrosis, all indicative of NAFLD. Genes involved in cell cycle, lysosome, ECM-receptor interaction, p53 and AGE-RAGE signaling pathways, and genes that are targeted by miR-335-5p, were over-expressed in WD male and female livers (p<0.05). Steroid biosynthesis pathway was however down-regulated in WD livers of both sexes. In WD male livers, PPAR signalling genes were up-regulated, while focal adhesion, amoebiasis and cytokine-cytokine receptor interaction pathways, and genes that are targeted by miR-133a-3p, miR-29b-3p and miR-199b-5p were up-regulated in WD female livers (p<0.05).
Conclusion: These data highlight miR-335-5p, lysosomes, control of hepatic cell-division cycle, ECM, AGE-RAGE system and steroid biosynthesis as central to early life NAFLD development and could be used to define biomarkers and to develop tools to calculate a lean NAFLD risk score.
Ting-Yim Lee– Professor, Departments of Medical Imaging, Medical Biophysics and Oncology, Robarts Research Institute, Lawson Health Research Institute, Western University.
Timothy Regnault– Associate Professor, Department of Physiology and Pharmacology, Lawson Health Research Institute, Children’s Health Research Institute.