Understanding Pathobiology of MASLD in Diabetic African Americans

The incidence of Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) has notably risen in recent years, reaching approximately 25–30% of the U.S. population by 2023. This alarming trend underscores the urgent need for research in this area. MASLD is a chronic condition characterized by hepatic fat accumulation (hepatic steatosis) combined with possible inflammation and progression to fibrosis, which is associated with underlying metabolic dysregulation. The reported incidence of MASLD among African Americans (AAs) in the US is low (13%) compared to the other population. However, AAs have a high incidence of risk factors associated with MASLD, often presenting with more aggressive and advanced stages of the disease at diagnosis. Our prior investigation identified the dysregulation of TGFB1 and E2F1 and related pathways in blood tissue samples from AA patients with early-stage MASLD. Our findings indicated the activation of the hepatic fibrosis signaling pathway toward the development of hepatocellular carcinoma (HCC) in MASLD patients. Still, the contribution of signature genes and their pathways to steatosis progression, specifically type 2 diabetes mellitus (T2DM) in AAs, is underexplored. Building on these lines of evidence, we hypothesize that AAs with T2DM exhibit distinct transcriptomic and genetic signatures related to inflammation, insulin resistance, and fibrosis, which affect the progression of hepatic steatosis and explain the lower risk in MASLD incidence despite high-metabolic risk factors prevalence. We propose this exploratory project to address these knowledge gaps and help to identify the genetic pathways disrupted by diabetes in the progression of MASLD in the AA population. It will improve our understanding of disease mechanisms in MASLD. Specific Aim1 is to comprehensively characterize the transcriptomic signatures and molecular pathways in T2DM and MASLD (T2DM with Steatosis) among African Americans. For this aim, the gene signature genetic variations and molecular pathways that contribute to the progression of hepatic steatosis in T2DM AAs will be identified as related to inflammation, insulin resistance, and fibrosis to determine the bio-functions Additionally, we will make a quick screening of the single nucleotide polymorphism (SNPs) of known MASLD-related variants (e.g., PNPLA3), to verify their role in liver disease progression, looking for the genetic differences among AA that explain lower MASLD incidence. Specific Aim 2 is to validate and correlate transcriptomic signatures with insulin resistance and inflammatory markers to examine their role in patients’ metabolic conditions and disease outcomes. we will validate the identified signature genes from Specific Aim 1 using qRT-PCR (high-throughput TaqMan Low-Density Array). Then we will correlate the status of inflammatory markers (e.g., TNF-α, IL-6, NF-κB) and insulin resistance using the HOMA-IR index, and other metabolic conditions retrieved from the patients EMR, with steatosis severity in AAs with T2DM and MASLD. We will apply logistic regression to classify and predict the prognosis associated with the expression of these signature genes, thereby quantifying future risk. This research will provide a strong foundation for an evidence-based RO1 study to understand the MASLD progression across the population. It will also identify actionable interventions to improve minority health and reduce health disparities with a vision of tailored therapies in the future.