Sterol regulatory element-binding proteins (SREBPs) are master transcription factors that play a crucial role in regulating genes involved in the biogenesis of cholesterol, fatty acids, and triglycerides. As such, they are implicated in several serious liver diseases, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). SREBPs are subject to regulation by multiple cofactors and critical signaling pathways, making them an important target for therapeutic interventions. In this review, we first introduce the structure and activation of SREBPs, before focusing on their function in liver disease. We examine the mechanisms by which SREBPs regulate lipogenesis, explore how alterations in these processes are associated with liver disease, and evaluate potential therapeutic strategies using small molecules, natural products, or herb extracts that target these pathways. Through this analysis, we provide new insights into the versatility and multitargets of SREBPs as factors in the modulation of different physiological stages of liver disease, highlighting their potential targets for therapeutic treatment.

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate genes involved in the biogenesis of cholesterol, fatty acids, and triglycerides. SREBPs are involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). We review the mechanisms by which SREBPs regulate lipogenesis, the alterations in these processes associated with liver diseases, and therapeutic strategies to target these pathways.

Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, we overview several crucial mechanisms related to ALD end-stage outcome development, such as epigenetic changes, cell death, hemolysis, hepatic stellate cells activation, and hepatic fatty acid binding protein 4. Additionally, in this review, we also present two clinically relevant models using human precision-cut liver slices and hepatic organoids to examine ALD pathogenesis and progression.

Here, we present a protocol for isolating human hepatocytes and neural progenitor cells from normal and nonalcoholic steatohepatitis livers. We describe steps for perfusion for scaled-up liver cell isolation and optimization of chemical digestion to achieve maximal yield and cell viability. We then detail a liver cell cryopreservation and potential applications, such as the use of human liver cells as a tool to link experimental and translational research.

Chronic liver injury results in activation of quiescent hepatic stellate cells (HSCs) into collagen type I–producing activated HSCs that make the liver fibrotic. We identified ETS1 and ETS2 (ETS1/2) as lineage-specific transcription factors regulating HSC phenotypes. Here, we investigated the role of ETS1/2 in HSCs in liver fibrosis using toxic liver injury models and 3D human liver spheroids. Liver fibrosis was induced in WT and HSC-specific Ets1-KO ( Ets1 ^ΔHSC ) and Ets2-KO ( Ets2 ^ΔHSC ) mice by administration of CCl ₄ for 6 weeks, followed by cessation of liver injury for 2 weeks. Liver fibrosis was more severe in Ets1 ^ΔHSC and to a lesser extent Ets2 ^ΔHSC mice compared with WT mice. Regression of liver fibrosis was suppressed only in Ets1 ^ΔHSC mice, indicating Ets1 is the predominant isoform maintaining a quiescent-like phenotype in HSCs. Similar results were obtained in a metabolic dysfunction–associated steatohepatitis (MASH) model using 3D human liver spheroids. Knockdown of ETS1 in human HSCs caused upregulation of fibrogenic genes in MASH human liver spheroids and prevented fibrosis regression. ETS1 regulated the quiescent HSC phenotype via the CREB-regulated transcription coactivator 2 (CRTC2)/PGC1α/PPARγ pathway. Knockdown of CRTC2 abrogated PPARγ responses and facilitated HSC activation. These findings suggest that ETS1 may represent a therapeutic target for antifibrotic therapy.