KLF15 regulates endobiotic and xenobiotic metabolism.
Shuxin HanJonathan W RayPreeti PathakDavid R SweetRongli ZhangHuiyun GaoNisha JainErik H KoritzinskyKeiichiro MatobaWeixiong XuE Ricky ChanDaniel I SimonMukesh K JainPublished in: Nature metabolism (2019)
Hepatic metabolism and elimination of endobiotics (for example, steroids, bile acids) and xenobiotics (for example, drugs, toxins) is essential for health. While the enzymatic (termed phase I-II) and transport machinery (termed phase III) controlling endobiotic and xenobiotic metabolism (EXM) is known, understanding of molecular nodal points that coordinate EXM function in physiology and disease remains incomplete. Here we show that the transcription factor Kruppel-like factor 15 (KLF15) regulates all three phases of the EXM system by direct and indirect pathways. Unbiased transcriptomic analyses coupled with validation studies in cells, human tissues, and animals, support direct transcriptional control of the EXM machinery by KLF15. Liver-specific deficiency of KLF15 (Li-KO) results in altered expression of numerous phase I-III targets, and renders animals resistant to the pathologic effects of bile acid and acetaminophen toxicity. Furthermore, Li-KO mice demonstrate enhanced degradation and elimination of endogenous steroid hormones, such as testosterone and glucocorticoid, resulting in reduced male fertility and blood glucose levels, respectively. Viral reconstitution of hepatic KLF15 expression in Li-KO mice reverses these phenotypes. Our observations identify a previously unappreciated transcriptional pathway regulating metabolism and elimination of endobiotics and xenobiotics.
Keyphrases
- transcription factor
- blood glucose
- phase iii
- poor prognosis
- dna binding
- gene expression
- clinical trial
- neoadjuvant chemotherapy
- ion batteries
- endothelial cells
- induced apoptosis
- public health
- high fat diet induced
- open label
- healthcare
- lymph node
- mental health
- long non coding rna
- genome wide identification
- health information
- single cell
- oxidative stress
- randomized controlled trial
- metabolic syndrome
- liver injury
- solid state
- signaling pathway
- skeletal muscle
- glycemic control
- weight loss
- heat shock
- drug induced
- insulin resistance
- placebo controlled
- cell proliferation
- pluripotent stem cells
- locally advanced
- rna seq
- cell cycle arrest
- single molecule