Sirtuin1 (SIRT1), which is regulated by microRNA-34a (miR-34a), can modulate pathophysiology processes, including nonalcoholic fatty liver disease and intestinal ischemia/reperfusion injury.
We identified four miRNAs overexpressed in obesity (miR-222, miR-142-3, miR-140-5p, and miR-143) and two miRNAs (miR-122 and miR-34a) overexpressed in children with obesity and nonalcoholic fatty liver disease (NAFLD) and/or insulin resistance.
The beneficial role of melatonin in dietary induced NAFLD/NASH in mice was related to reduced expression of microRNA-34a-5p and sterol regulatory element-binding protein (SREBP1) but only in the presence of full SIRT1 availability.
In conclusion, the decrease of Mirt2 expression contributed to hepatic insulin resistance and steatosis in obese mice, and Mirt2/miR-34a-5p/USP10 was involved in NAFLD development.
In the present study, we have re-examined the predictive value of these serum microRNAs and found that 9 of them (miR-34a, -192, -27b, -122, -22, -21, -197, -30c and -16) associated to NAFLD severity in our independent cohort.
The diagnostic value of miR-34a for NASH (area under the receiver operating characteristic, 0.811, 95%CI: 0.670-0.953) was superior to that of alanine aminotransferase, CK-18, FIB-4 and APRI in NAFLD, but miR-16 showed a limited performance in the diagnosis of significant fibrosis in NASH.
Notably, CRTC1 also mediates anti-lipogenic effects of bile acid signaling, whereas it is negatively regulated by miR-34a, a pathogenic microRNA upregulated in a broad spectrum of NAFLD.
These data indicate that the miR-34a-HNF4α pathway is activated under common conditions of metabolic stress and may have a role in the pathogenesis of NAFLD and in regulating plasma lipoprotein metabolism.
Cholesterol synthesis was increased as measured by the circulating desmosterol:cholesterol ratio. miR-34a, a microRNA increased in NAFLD, inhibited sirtuin-1 with downstream dephosphorylation of AMP kinase and HMGCR.
Serum levels of miR-34a and miR-122 may represent novel, noninvasive biomarkers of diagnosis and histological disease severity in patients with CHC or NAFLD.