RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network

Abstract

The retinoic acid receptor-related orphan receptor-α (RORα) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic RORα controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-γ (PPARγ) that mediates hepatic lipid metabolism. Liver-specific Rorα-deficient mice develop hepatic steatosis, obesity and insulin resistance when challenged with a high-fat diet (HFD). Global transcriptome analysis reveals that liver-specific deletion of Rorα leads to the dysregulation of PPARγ signaling and increases hepatic glucose and lipid metabolism. RORα specifically binds and recruits histone deacetylase 3 (HDAC3) to PPARγ target promoters for the transcriptional repression of PPARγ. PPARγ antagonism restores metabolic homeostasis in HFD-fed liver-specific Rorα deficient mice. Our data indicate that RORα has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate RORα activity may be beneficial for the treatment of metabolic disorders.

MicroRNA‐10a Impairs Liver Metabolism in Hepatitis C Virus‐Related Cirrhosis Through Deregulation of the Circadian Clock Gene Brain and Muscle Aryl Hydrocarbon Receptor Nuclear Translocator‐Like 1

“…Similar results were observed under oleic acid treatment. By contrast, the expression of PPARG , reported to be inhibited by RORA , remained relatively unaffected by the overexpression or knockdown of miR‐10a (Fig. B).…”

“…The supervised learning method (BRB-ArrayTools; National Center for Biotechnology Information) was used to examine whether 41 patients were classified according to each clinical category using differentially expressed predictor miRNAs (P < 0.05). Based on histology (stage, activity, and steatosis), age, sex, levels of ALT, amount of HCV-RNA, interleukin-28B genotype, and treatment response to pegylated interferon (PEG-IFN)+ribavirin (RBV) therapy, each predictor was identified (55, 38,17,11,4, 50, 1, 3, and 7 miRNAs, respectively). However, only 55 predictors according to histologic progression (F12 vs. F34) could accurately classify the patients (P < 0.002) ( Supporting Table S1).…”

Cis‐9, Trans‐11 Conjugated Linoleic Acid Reduces Phosphoenolpyruvate Carboxykinase Expression and Hepatic Glucose Production in HepG2 Cells

“…In nonadipose cells, forced expression of PPARγ is able to activate the PEPCK‐C enhancer of the said cells (Tontonoz et al, ). PPARγ antagonist GW 9662 has been shown to inhibit PEPCK expression in vivo (Kim et al, ). GW 9662 binds to PPARγ at an IC 50 of 3.3 nM (Leesnitzer et al, ), therefore, we reasoned that the reduction of HGP in the presence of GW 9662 is attributed to inhibition of PPARγ binding to PPARE instead of CLA activation.…”

Mitochondrial and anabolic pathways in hepatocellular carcinoma

“…Hepatocellular carcinoma (HCC) is one of the leading liver cancers that affects many patients of different ages . Numerous mutational studies and studies of global transcriptome and proteome have emphasized extraordinary complexity of alterations that are observed in cancer cells . The liver is a key tissue in metabolic homeostasis regulation, and recent discoveries have shown that certain metabolic alterations are critical in the development of HCC .…”

“…Numerous mutational studies and studies of global transcriptome and proteome have emphasized extraordinary complexity of alterations that are observed in cancer cells . The liver is a key tissue in metabolic homeostasis regulation, and recent discoveries have shown that certain metabolic alterations are critical in the development of HCC . However, very little is known about the specific mechanisms and key factors that drive the metabolic‐dependent pathways of HCC.…”