545회 정기세미나_김경진 교수님(인하대)

Kctd17, a novel regulator in hepatic insulin resistance and nonalcoholic fatty liver diseases

김경진 교수(인하대학교 의과대학)

Obesity-induced fatty liver predisposes to non-alcoholic steatohepatitis (NASH), which has no approved pharmacotherapy, making it the fastest growing indication for liver transplantation. Fatty liver develops in part due to excess hepatic de novo lipogenesis (DNL), an insulin-stimulated cell-autonomous synthesis of fatty acids, a conundrum as obesity is commonly associated with insulin resistance and glucose intolerance. We show that the serine/threonine phosphatase PHLPP2 terminates insulin action in the liver by dephosphorylating Akt Ser473 to repress DNL but not gluconeogenic pathways. In obesity, endogenous PHLPP2 is degraded – to understand this regulation, we performed LC-MS/MS which identified glucagon/PKA-dependent PHLPP2 phosphorylations at Ser1119 and Ser1210, which recruit the adaptor KCTD17 and ubiquitin E3 ligase Cullin3. Hepatic Kctd17 expression is increased in murine obesity, and KCTD17 is correlated with excess hepatic fat in patients. Knockdown of hepatic Kctd17 in obese mice prevents PHLPP2 degradation, allowing repression of DNL and fat accumulation, while overexpression of Kctd17 in healthy mice provokes fatty liver. These results demonstrate that modulators of the PHLPP2/KCTD17 axis can reverse obesity-induced hepatic steatosis and may be utilized to treat NASH.

학력 및 약력

2000-2004   부산대학교 분자생물학과, 이학사

2004-2006   부산대학교 분자생물학과, 이학석사

2006-2010   부산대학교 분자생물학과, 이학박사

2010-2013   성균관대학교 의과대학, 박사후연구원

2013-2019   Postdoctoral Research Scientist/Associate Research Professor, Columbia University Medical Center, USA아

2019-현재   인하대학교 의과대학, 조교수

주요발표논문 (최근)

1. Kim K*, Kang JK, Jung YH, Lee SB, Rametta R, Dongiovanni P, Valenti L, Pajvani UB. Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver. Nature Communications. 2021 Mar 23: 12(1): 1822 (*Coresponding author).

2 Kim K, Yang WH, Jung YS, Cha JH. A new aspect of an old friend: the beneficial effect of metformin on antitumor immunity. BMB Reports. 2020 Nov;53(10):512-520.

3. Kim K*, Kim KH. Targeting of Secretory Proteins as a Therapeutic Strategy for Treatment of Nonalcoholic Steatohepatitis (NASH). Int J Mol Sci. 2020 Mar 26; 21(7): 2296 (*Co-responding author)

4. Kim K, Goldberg IJ, Graham MJ, Sundaram M, Bertaggia E, Lee SX, Qiang L, Haeusler RA, Metzger D, Chambon P, Yao Z, Ginsberg HN, Pajvani UB. Gamma-secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor. Cell Metabolism 2018 Apr 3; 27(4): 816-827.e4

5. Kim K, Ryu D, Dongiovanni P, Ozcan L, Nayak S, Ueberheide B, Valenti L, Auwerx J, Pajvani UB. Degradation of PHLPP2 by KCTD17, via a Glucagon-dependent Pathway, Promotes Hepatic Steatosis. Gastroenterology 2017. Dec;153(6):1568-1580.e10

6.Kim K, Pajvani UB. “Free” Raptor – a novel regulator of metabolism. Cell Cycle 2016. May 2;15(9):1174-5

7. Kim K, Qiang L, Hayden MS, Sparling D, Purcell N, Pajvani UB. mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2. Nature Communications 2016. Jan 8;7:10255