Repression of the Nuclear Receptor Small Heterodimer Partner by Steatotic Drugs and in Advanced Nonalcoholic Fatty Liver Disease

Abstract

The small heterodimer partner (SHP) (NR0B2) is an atypical nuclear receptor that lacks a DNA-binding domain. It interacts with and inhibits many transcription factors, affecting key metabolic processes, including bile acid, cholesterol, fatty acid, and drug metabolism. Our aim was to determine the influence of steatotic drugs and nonalcoholic fatty liver disease (NAFLD) on SHP expression and investigate the potential mechanisms. SHP was found to be repressed by steatotic drugs (valproate, doxycycline, tetracycline, and cyclosporin A) in cultured hepatic cells and the livers of different animal models of NAFLD: iatrogenic (tetracycline-treated rats), genetic (glycine N-methyltransferase-deficient mice), and nutritional (mice fed a methionine-and choline-deficient diet). Among the different transcription factors investigated, CCAATenhancer-binding protein a (C/EBPa) showed the strongest dominant-repressive effect on SHP expression in HepG2 and human hepatocytes. Reporter assays revealed that the inhibitory effect of C/EBPa and steatotic drugs colocalize between 2340 and 2509 base pair of the SHP promoter, and mutation of a predicted C/EBPa response element at 2473 base pair abolished SHP repression by both C/EBPa and drugs. Moreover, inhibition of major stress signaling pathways demonstrated that the mitogen-activated protein kinase kinase 1/2 pathway activates, while the phosphatidylinositol 3 kinase pathway represses SHP in a C/EBP-dependent manner. We conclude that SHP is downregulated by several steatotic drugs and in advanced NAFLD. These conditions can activate signals that target C/EBPa and consequently repress SHP, thus favoring the progression and severity of NAFLD.

A Network Involving Gut Microbiota, Circulating Bile Acids, and Hepatic Metabolism Genes That Protects Against Non‐Alcoholic Fatty Liver Disease

“…Isolation of total RNA, cDNA synthesis, and quantitative real‐time PCR (qPCR) from mouse livers were performed essentially as in Benet et al . Sequences of each primer pair are provided in Table S5, Supporting Information.…”

Interplay of lamin A and lamin B LADs on the radial positioning of chromatin

“…Drug-induced hepatotoxicity, a common cause of clinical trial failure, has led to the use of cellular models such as HepG2 hepatocarcinoma cells for drug testing [1,2]. At micromolar concentrations, the steatotic drug cyclosporin A (CsA) inhibits several signaling pathways in HepG2 cells [3], resulting in metabolic alterations [1,3,4]. Interestingly, CsA can also act by modulating the binding of transcription factors to chromatin [3], suggesting an impact on genome organization.…”

Circadian rhythmicity: A functional connection between differentiated embryonic chondrocyte-1 (DEC1) and small heterodimer partner (SHP)

“…To complement the transfection study, we next tested whether SHP and DEC1 are inversely regulated for their oscillating expression by valproate, a widely used antiepileptic that was established to down-regulate SHP [38]. Importantly, valproate is a steatotic agent and both DEC1 and SHP are metabolic regulators.…”