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Autophagy, Published online: 17 May 2018 | https://doi.org/10.1080/15548627.2018.1448326 Ciliogenesis is reciprocally regulated by PPARA and NR1H4/FXR through controlling autophagy in vitro and in vivo

Zhi-qiang Liu^a*, Joon No Lee^b*, Myeongjoo Son^d,e, Jae-Young Lim^a, Raghbendra Kumar Dutta^a, Yunash Maharjan^a, SeongAe Kwak^c, Goo Taeg Oh^f, Kyunghee Byun^d,e, Seong-Kyu Choe^a and Raekil Park^b^aDepartment of Microbiology and Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan, Jeonbuk, Korea;
^bDepartment of Biomedical Science & Engineering, Institute of Integrated Technology, Gwangju Institute of Science & Technology, Gwangju, Korea;
^cZoonosis Research Center, Wonkwang University School of Medicine, Iksan, Jeonbuk, Korea;
^dDepartment of Anatomy and Cell Biology, Gachon University Graduate School of Medicine, Incheon, Korea; ^eFunctional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea;
^fLaboratory of Cardiovascular Genomics, Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea
^*These authors contributed equally to this work.

Address correspondence to Raekil Park

Abstract

The primary cilia are evolutionarily conserved microtubule-based cellular organelles that perceive metabolic status and thus link the sensory system to cellular signaling pathways. Therefore, ciliogenesis is thought to be tightly linked to autophagy, which is also regulated by nutrient-sensing transcription factors, such as PPARA (peroxisome proliferator activated receptor alpha) and NR1H4/FXR (nuclear receptor subfamily 1, group H, member 4). However, the relationship between these factors and ciliogenesis has not been clearly demonstrated. Here, we present direct evidence for the involvement of macroautophagic/autophagic regulators in controlling ciliogenesis. We showed that activation of PPARA facilitated ciliogenesis independently of cellular nutritional states. Importantly, PPARA-induced ciliogenesis was mediated by controlling autophagy, since either pharmacological or genetic inactivation of autophagy significantly repressed ciliogenesis. Moreover, we showed that pharmacological activator of autophagy, rapamycin, recovered repressed ciliogenesis in ppara^-/- cells. Conversely, activation of NR1H4 repressed cilia formation, while knockdown of NR1H4 enhanced ciliogenesis by inducing autophagy. The reciprocal activities of PPARA and NR1H4 in regulating ciliogenesis were highlighted in a condition where de-repressed ciliogenesis by NR1H4 knockdown was further enhanced by PPARA activation. The in vivo roles of PPARA and NR1H4 in regulating ciliogenesis were examined in greater detail in ppara^-/- mice. In response to starvation, ciliogenesis was facilitated in wild-type mice via enhanced autophagy in kidney, while ppara^-/- mice displayed impaired autophagy and kidney damage resembling ciliopathy. Furthermore, an NR1H4 agonist exacerbated kidney damage associated with starvation in ppara^-/- mice. These findings indicate a previously unknown role for PPARA and NR1H4 in regulating the autophagy-ciliogenesis axis in vivo.

KEYWORDS: autophagy, ciliogenesis, kidney, NR1H4/FXR, PPARA

논문정보

형식Research article
게재일2018년 05월 (BRIC 등록일 2018-05-25)
연구진국내 연구진
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