HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation

Abstract

Disregulation of fatty acid oxidation, one of the major mechanisms for maintaining hepatic lipid homeostasis under fasting conditions, leads to hepatic steatosis. Although obesity and type 2 diabetes-induced endoplasmic reticulum (ER) stress contribute to hepatic steatosis, it is largely unknown how ER stress regulates fatty acid oxidation. Here we show that fasting glucagon stimulates the dephosphorylation and nuclear translocation of histone deacetylase 5 (HDAC5), where it interacts with PPARα and promotes transcriptional activity of PPARα. As a result, overexpression of HDAC5 but not PPARα binding-deficient HDAC5 in liver improves lipid homeostasis, whereas RNAi-mediated knockdown of HDAC5 deteriorates hepatic steatosis. ER stress inhibits fatty acid oxidation gene expression via calcium/calmodulin-dependent protein kinase II-mediated phosphorylation of HDAC5. Most important, hepatic overexpression of a phosphorylation-deficient mutant HDAC5 2SA promotes hepatic fatty acid oxidation gene expression and protects against hepatic steatosis in mice fed a high-fat diet. We have identified HDAC5 as a novel mediator of hepatic fatty acid oxidation by fasting and ER stress signals, and strategies to promote HDAC5 dephosphorylation could serve as new tools for the treatment of obesity-associated hepatic steatosis.

Peroxisome Proliferator Activated Receptor Agonists Modulate Transposable Element Expression in Brain and Liver

“…There is also evidence of the inverse relationship, that is, that histone marks regulate PPARs and response to PPAR agonists. Hdac5 is dephosphorylated and translocated to the nucleus by fasting-induced rises in glucagon levels where it interacts with PPARα to promote its transcriptional activity, thereby mediating hepatic fatty acid oxidation by fasting and ER stress ( Qiu et al, 2017 ). The histone H3 lysine 4 methyltransferase, Mll4/Kmt2d, directs overnutrition-induced murine steatosis via its coactivator function for PPARγ2, whereby overnutrition activates Abl1 kinase which phosphorylates PPARγ2, and hence has enhanced interaction with Mll4 ( Kim et al, 2016 ).…”

BMAL1 functions as a cAMP-responsive coactivator of HDAC5 to regulate hepatic gluconeogenesis

“…Gluconeogenesis is one of the major mechanisms to maintain hepatic glucose homeostasis and dysregulation of hepatic gluconeogenesis contributes to hyperglycemia in type 2 diabetes. Under fasted conditions, increases in circulating glucagon promote hepatic glucose production through activation of gluconeogenic pathway by HDAC5 and CREB coactivator CRTC2 (Lv et al, 2016 ; Lv et al, 2017 ; Qiu et al, 2017 ). The circadian clock coordinates behavior and metabolism into rhythms not only in the central hypothalamus but also in peripheral tissues (Marcheva et al, 2010 ; Vollmers et al, 2009 ).…”

A Novel Biomarker TLCD1 Correlates With Prognosis and Immune Infiltrates in Hepatocellular Carcinoma

“…Firstly, the variations in TLCD1 expression level related to prognosis and in ltration of immune cells in HCC were determined. Responding to the hormonal signals, the major organ, the liver controls the glucose and the lipid metabolism 29 . The action of TLCD1 at the level of the plasma membrane by limiting the amounts of LCPUFA-containing phospholipids was suggested by the previous study 7 .…”