IDDF2021-ABS-0138 Circulating non-coding transcripts serving as biomarkers for diabetic liver steatosis

BackgroundNon-alcoholic steatohepatitis (NASH) as an advanced form of NAFLD is associated with excessive inflammation in the steatotic livers. Given the common co-morbidity of NASH with diabetes mellitus (DM), we identified a set of circulating RNA transcripts as non-invasive biomarkers to classify disease phenotypes relevant to the onset of diabetic steatosis followed by progression towards liver inflammation.MethodsWe compared miR-192-3p level in mice given HFD (high-fat diet), HFFD (high-fat fructose diet), and MCD (methionine-choline deficient diet) diets. Histopathological lesions were analyzed at critical stages to correlate the miRNA expression. In obese individuals diagnosed with DM or not, we examined the miR-192-3p level by droplet digital PCR and characterized serum whole transcriptomes with SEQuoia Complete Stranded RNA Library kits.ResultsAlong with our reported loss of the overlooked star strand miR-192-3p in db/db mice, we found a high circulating level of miR-192-3p in different diets-induced animals, indicating a heightened inflammatory response in the liver, especially in those given HFFD and MCD diets. Since circulating miR-192-3p surges only in HFFD under an insulin-resistant state but not manifested at all in HFD, its circulating level shall reflect the extent of runaway glycerolipid metabolism. Indeed, we observed a similar expression pattern in serum miR-192-3p for obese individuals (BMI>34), where the miRNA can only be detected in individuals diagnosed with DM. Our transcriptomic analysis identified that PI3K-Akt signaling, FoxO signaling and TGFβ signaling pathways were enriched in the hepatocytes with miR-192-3p overexpression. The top differential circulating non-coding transcripts between those individuals with or without diabetes belonged to the ribosomal pathway under the modulating actions of Akt, suggesting the use of these transcripts for a better account of diabetic phenotype.ConclusionsCirculating levels of miR-192-3p and transcripts along its regulated Akt pathway account for visceral obesity and reflect prognostic outcomes to the progression of diabetes. We hereby advocate miR-192-3p as a functional glycerolipid regulator for steatosis in the diabetic liver which offers know-how for better disease staging and treatment regimes.