Gain-of-Function Mutations of SLC16A11 Contribute to the Pathogenesis of Type 2 Diabetes

Yongxu Zhao; Zhuanghui Feng; Yongxian Zhang; Yingmin Sun; Yanhao Chen; Xiaojian Liu; Shuang Li; Tingting Zhou; Lanlan Chen; Yuda Wei; Danjun Ma; Kathy O Lui; Hao Ying; Yan Chen; Qiurong Ding

doi:10.1016/j.celrep.2018.12.100

Gain-of-Function Mutations of SLC16A11 Contribute to the Pathogenesis of Type 2 Diabetes

Cell Rep. 2019 Jan 22;26(4):884-892.e4. doi: 10.1016/j.celrep.2018.12.100.

Authors

Yongxu Zhao¹, Zhuanghui Feng², Yongxian Zhang², Yingmin Sun², Yanhao Chen², Xiaojian Liu², Shuang Li², Tingting Zhou², Lanlan Chen², Yuda Wei², Danjun Ma³, Kathy O Lui⁴, Hao Ying², Yan Chen², Qiurong Ding⁵

Affiliations

¹ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, PRC; College of Mechanical Engineering, Dongguan University of Technology, Dongguan, Guangdong 523808, PRC.
² CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, PRC.
³ College of Mechanical Engineering, Dongguan University of Technology, Dongguan, Guangdong 523808, PRC.
⁴ Department of Chemical Pathology and Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, PRC.
⁵ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, PRC; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, PRC. Electronic address: [email protected].

PMID: 30673611
DOI: 10.1016/j.celrep.2018.12.100

Abstract

DNA variants in the SLC16A11 coding region were identified to be strongly associated with type 2 diabetes (T2DM) in a Mexican population. Previous studies suggested that these variants disrupt SLC16A11 function and therefore proposed to revive SLC16A11 levels or activity to achieve therapeutic benefit. However, with knockout mouse models, here we show that Slc16a11 depletion has no significant metabolic defects. Further studies demonstrate that reconstitution of the mutant, but not the wild-type Slc16a11, in the liver of knockout mice causes more triglyceride accumulation and induction of insulin resistance via upregulation of lipin 1, suggesting gaining of aberrant functions of the mutant protein that affects lipid metabolism. Our findings offer a different explanation to the function of these diabetic variants, challenging the concept of enhancing SLC16A11 function to treat T2DM. The contradictory results by our and previous studies suggest that how the SLC16A11 locus contributes to human metabolism warrants further investigation.

Keywords: Lipin 1; SLC16A11; triglyceride metabolism; type 2 diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Experimental* / genetics
Diabetes Mellitus, Experimental* / metabolism
Diabetes Mellitus, Experimental* / pathology
Diabetes Mellitus, Type 2* / genetics
Diabetes Mellitus, Type 2* / metabolism
Diabetes Mellitus, Type 2* / pathology
Gain of Function Mutation*
HEK293 Cells
Humans
Insulin Resistance / genetics*
Mice
Mice, Knockout
Monocarboxylic Acid Transporters* / genetics
Monocarboxylic Acid Transporters* / metabolism
Phosphatidate Phosphatase / genetics
Phosphatidate Phosphatase / metabolism
Triglycerides* / genetics
Triglycerides* / metabolism

Substances

Monocarboxylic Acid Transporters
Triglycerides
Lpin1 protein, mouse
Phosphatidate Phosphatase