Hepatic Krüppel-like factor 16 (KLF16) targets PPARα to improve steatohepatitis and insulin resistance

Abstract

ObjectiveImpaired hepatic fatty acids oxidation results in lipid accumulation and redox imbalance, promoting the development of fatty liver diseases and insulin resistance. However, the underlying pathogenic mechanism is poorly understood. Krüppel-like factor 16 (KLF16) is a transcription factor that abounds in liver. We explored whether and by what mechanisms KLF16 affects hepatic lipid catabolism to improve hepatosteatosis and insulin resistance.DesignKLF16 expression was determined in patients with non-alcoholic fatty liver disease (NAFLD) and mice models. The role of KLF16 in the regulation of lipid metabolism was investigated using hepatocyte-specific KLF16-deficient mice fed a high-fat diet (HFD) or using an adenovirus/adeno-associated virus to alter KLF16 expression in mouse primary hepatocytes (MPHs) and in vivo livers. RNA-seq, luciferase reporter gene assay and ChIP analysis served to explore the molecular mechanisms involved.ResultsKLF16 expression was decreased in patients with NAFLD, mice models and oleic acid and palmitic acid (OA and PA) cochallenged hepatocytes. Hepatic KLF16 knockout impaired fatty acid oxidation, aggravated mitochondrial stress, ROS burden, advancing hepatic steatosis and insulin resistance. Conversely, KLF16 overexpression reduced lipid deposition and improved insulin resistance via directly binding the promoter of peroxisome proliferator-activated receptor α (PPARα) to accelerate fatty acids oxidation and attenuate mitochondrial stress, oxidative stress in db/db and HFD mice. PPARα deficiency diminished the KLF16-evoked protective effects against lipid deposition in MPHs. Hepatic-specific PPARα overexpression effectively rescued KLF16 deficiency-induced hepatic steatosis, altered redox balance and insulin resistance.ConclusionsThese findings prove that a direct KLF16–PPARα pathway closely links hepatic lipid homeostasis and redox balance, whose dysfunction promotes insulin resistance and hepatic steatosis.

Systematic Identification and Comparison of the Expressed Profiles of lncRNAs, miRNAs, circRNAs, and mRNAs with Associated Co-Expression Networks in Pigs with Low and High Intramuscular Fat

“…Although we constructed the DE circRNA–miRNA–DE mRNA, DE lncRNA–miRNA–DE mRNA, and DE circRNA–miRNA–DE lncRNA networks based on the “sponge adsorption” theory, the results showed that the genes were mainly involved in immune regulation and anti-infection. According to previous research results, these signaling pathways and key genes are also widely involved in lipid metabolism and fat deposition [ 60 , 61 , 62 ]. These may play an important role in the complex molecular process of intramuscular fat deposition.…”

Hepatic SIRT6 Modulates Transcriptional Activities of FXR to Alleviate Acetaminophen-induced Hepatotoxicity

“…Liver samples from biopsy and preoperative testing for obstructive jaundice-induced acute liver injury were collected from the First Affiliated Hospital of Guangzhou University of Chinese Medicine as previously reported. 56 Written informed consent was obtained from all patients involved in this study. The protocol for clinical tissue preparation was approved by the ethics committees of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (No: ZYYECK(2019)008) and subject to the guidelines of the 1975 Declaration of Helsinki.…”

Current Options and Future Directions for NAFLD and NASH Treatment

“…In addition, there are some other targets for NAFLD and NASH treatments, such as G protein-coupled receptors ( GPCRs ) [ 142 ], estrogen-related receptor alpha ( ERRα ) [ 143 ], bone morphogenetic proteins ( BMPs ) [ 144 ], and KLFs [ 24 , 145 ]. The treatment options for NAFLD/NASH are summarized in the graphic picture ( Figure 2 ).…”