Tumor necrosis factor and interleukin 1 decrease RXRα, PPARα, PPARγ, LXRα, and the coactivators SRC-1, PGC-1α, and PGC-1β in liver cells

Abstract

During the acute phase response (APR), cytokines induce marked alterations in lipid metabolism including an increase in serum triglycerides, a decrease in hepatic fatty acid oxidation, a decrease in bile acid synthesis, and a decrease in HDL. Here we demonstrate that TNF and IL-1, but not IL-6, decrease the expression of RXRα, PPARα, PPARγ, LXRα and coactivators PGC-1α, PGC-1β and SRC-1 in Hep3B human hepatoma cells. Additionally, treatment of mice with TNF and IL-1 also decreased RXRα, PPARα, PPARγ, LXRα, and PGC-1α mRNA levels in the liver. These decreases were accompanied by reduced binding of nuclear extracts to RXR, PPAR, and LXR response elements and decreased luciferase activity driven by PPAR and LXR response elements. In addition, the mRNA levels of proteins regulated by PPARα (CPT 1α) and LXR (SREBP-1c) were decreased in Hep 3B cells treated with TNF or IL-1. Finally, using constructs of the LXRα promoter or the PGC-1α promoter linked to luciferase we were able to demonstrate that a decrease in transcription contributes to the reduction in mRNA levels of nuclear hormone receptors and coactivators. Thus, our results suggest that decreased expression of nuclear hormone receptors RXRα, PPARα, PPARγ, and LXRα, as well as coactivators PGC-1α, PGC-1β, and SRC-1 may contribute to the cytokine induced alterations in hepatic lipid metabolism during the APR.

Modification in Oxidative Stress, Inflammation, and Lipoprotein Assembly in Response to Hepatocyte Nuclear Factor 4α Knockdown in Intestinal Epithelial Cells

“…Results similar to ours have been found in liver cells, where TNF-␣ and IL-1 caused a marked decrease in retinoid X receptor ␣, PPAR␣, PPAR␥, LXR␣ and SREBP-1c (97). In the liver of apoE knockout mice and in HepG2 cells, inflammatory stress inhibited PPAR␣ and LXR␣ but increased cholesterol accumulation and SREBP-2 (98).…”

The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction

“…Type I and type II interferons, tumor necrosis factor, interleukin-12, energy charge, and low NAD + /NADH or oleate/ palmitate ratios have been shown to repress PGC1α expression, localization or transcriptional activity through a variety of signaling pathways (Alvarez-Guardia et al, 2010;Haghikia et al, 2015;Kauppinen et al, 2013;Kim et al, 2007b;Palomer et al, 2009;Scarpulla, 2011). PGC1α is post-translationally modified by a number of signaling pathways important in T cell biology (Akt, p38-MAPK, AMPK, SIRT1, PRMT1) (Fernandez-Marcos and Auwerx, 2011).…”

Down-regulation of SREBP-1c is associated with the development of burned-out NASH

“…It is reported that LXR, RXR, insulin, and pro-inflammatory cytokines, such as TNF- and IL-1, can modulate the mRNA levels of SREBP-1c [20,30].…”