Exploring the Regulatory Role of ncRNA in NAFLD: A Particular Focus on PPARs

Abstract

Liver diseases are responsible for global mortality and morbidity and are a significant cause of death worldwide. Consequently, the advancement of new liver disease targets is of great interest. Non-coding RNA (ncRNA), such as microRNA (miRNA) and long ncRNA (lncRNA), has been proven to play a significant role in the pathogenesis of virtually all acute and chronic liver disorders. Recent studies demonstrated the medical applications of miRNA in various phases of hepatic pathology. PPARs play a major role in regulating many signaling pathways involved in various metabolic disorders. Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, encompassing a spectrum spanning from mild steatosis to severe non-alcoholic steatohepatitis (NASH). PPARs were found to be one of the major regulators in the progression of NAFLD. There is no recognized treatment for NAFLD, even though numerous clinical trials are now underway. NAFLD is a major risk factor for developing hepatocellular carcinoma (HCC), and its frequency increases as obesity and diabetes become more prevalent. Reprogramming anti-diabetic and anti-obesity drugs is an effective therapy option for NAFLD and NASH. Several studies have also focused on the role of ncRNAs in the pathophysiology of NAFLD. The regulatory effects of these ncRNAs make them a primary target for treatments and as early biomarkers. In this study, the main focus will be to understand the regulation of PPARs through ncRNAs and their role in NAFLD.

LncRNASnhg3Aggravates Hepatic Steatosis via PPARγ Signaling

“…PPARγ expression. Clinical trials have indicated that increased insulin resistance and hepatic PPARγ expressions were associated with NASH scores in some obese patients(Lee, Muratalla et al, 2023a, Mukherjee, Wanjari et al, 2022. Activation of PPARγ in the liver induces the adipogenic program to store fatty acids in lipid droplets as observed in adipocytes (Lee et al, 2018).…”

“…In this study, Snhg3 overexpression induced an increase in hepatic PPARγ and CD36.Although the administration of PPARγ antagonist T0070907 aggravated hepatic steatosis owing to an inhibition of adipogenesis in adipose tissue, it improved Snhg3-induced hepatic steatosis. Even though PPARγ's primary function is in adipose tissue, patients with MASLD have much higher hepatic expression levels of PPARγ, reflecting the fact that PPARγ plays different roles in different tissues and cell types(Mukherjee et al, 2022). Thus, understanding how the hepatic PPARγ expression is regulated will help develop prevention and treatments for MASLD(Lee et al, 2018).Epigenetics plays a crucial role in many physiological and pathological situations(Peixoto, Cartron et al, 2020).…”

“…Lee, Muratalla et al, 2023a, Mukherjee, Wanjari et al, 2022. Activation of PPARγ in the liver induces the adipogenic program to store fatty acids in lipid droplets as observed in adipocytes (Lee et al, 2018).…”

“…This study demonstrated that lncRNA-Snhg3 participated in the pathology of MASLD by epigenetic modification; that is, Snhg3 inhibited the H3K27me3 level, and promoted chromatin relaxation at the Pparγ promoter and eventually increased PPARγ expression. The results from Ruan et al demonstrated that more than a third of dynamically expressed lncRNAs were deregulated in a human MASLD cohort and the lncRNA human lncRNA metabolic regulator 1 (hLMR1) positively regulated transcription of genes involved in cholesterol metabolism(Ruan, Li et al, 2021).Previous studies have also demonstrated that several lncRNAs, including FLRL2/3/6/7/8, H19, and MALAT-1, were associated with lipogenesis via proteins in the PPAR signaling pathway(Mukherjee et al, 2022). Recently, a murine long noncoding single-cell transcriptome analysis elucidated liver lncRNA cell-type specificities, spatial zonation patterns, associated regulatory networks, and temporal patterns of dysregulation during hepatic disease progression.…”

Recent Insights into the Role of PPARs in Disease

“…Mukherjee et al summarize the role of PPARs and non-coding RNAs in non-alcoholic fatty liver disease (NAFLD) [ 44 ]. They introduce the causes and pathology of NAFLD and describe the roles of the different PPAR isoforms in this disease.…”