Identification of novel targets in adipose tissue involved in non‐alcoholic fatty liver disease progression

Abstract

Obesity is a major risk factor for the development of Nonalcoholic fatty liver disease (NAFLD). We hypothesize that a dysfunctional subcutaneous white adipose tissue (scWAT) may lead to an accumulation of ectopic fat in the liver. Our aim was to investigate the molecular mechanisms involved in the causative role of scWAT in NALFD progression. We performed a RNA‐sequencing analysis in a discovery cohort (n = 45) to identify genes in scWAT correlated with fatty liver index, a qualitative marker of liver steatosis. We then validated those targets in a second cohort (n = 47) of obese patients who had liver biopsies available. Finally, we obtained scWAT mesenchymal stem cells (MSCs) from 13 obese patients at different stages of NAFLD and established in vitro models of human MSC (hMSC)‐derived adipocytes. We observed impaired adipogenesis in hMSC‐derived adipocytes as liver steatosis increased, suggesting that an impaired adipogenic capacity is a critical event in the development of NAFLD. Four genes showed a differential expression pattern in both scWAT and hMSC‐derived adipocytes, where their expression paralleled steatosis degree: SOCS3, DUSP1, SIK1, and GADD45B. We propose these genes as key players in NAFLD progression. They could eventually constitute potential new targets for future therapies against liver steatosis.

Evidence That Peripheral Leptin Resistance in Omental Adipose Tissue and Liver Correlates with MASLD in Humans

“…SOCS3 plays a role in liver insulin resistance and increased inflammation that accelerates simple steatosis [ 134 ]. SOCS3 expression in adipose tissue is parallel to the degree of steatosis [ 135 ], SOCS3 , is regulated by microRNA-650, and controls JAK/STAT3 signaling, posing a risk factor for MASLD and hepatocellular carcinoma [ 136 ]. SOCS3 negatively regulates insulin and leptin signaling [ 137 ].…”

Shared Genes and Molecular Mechanisms between Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma Established by WGCNA Analysis

“…26 Lopez-Yus et al reported that the expression of DUSP1 paralleled the degree of steatosis, and DUSP1 could be a key player in the progression of NAFLD. 27 JUNB, a member of the Fos/Jun family, is a key component of activator protein transcription factors and a major target element of mitotic activation and transmission pathways. 28 Previous studies have found that JUNB negatively regulated cell proliferation and Ras-mediated malignant transformation while also participating in proapoptotic pathways.…”

“… 26 Lopez-Yus et al reported that the expression of DUSP1 paralleled the degree of steatosis, and DUSP1 could be a key player in the progression of NAFLD. 27 …”

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies

“…Changes in leptin signaling in patients with NAFLD are related to the pathophysiology of this disease; thus, the association of polymorphisms in the leptin receptor gene with NAFLD has been described [ 257 ]. In addition, mesenchymal stem cell-derived adipocytes from obese patients at different stages of NAFLD have impaired adipogenesis as liver steatosis augmented, showing a differential expression pattern in SOCS3, comparable to steatosis degree [ 258 ]. Different data in animals and humans show a relationship of certain miRNAs with hepatic metabolic homeostasis and leptin signaling.…”