DHHC4 and DHHC5 Facilitate Fatty Acid Uptake by Palmitoylating and Targeting CD36 to the Plasma Membrane

Juan Wang, Jian Wei Hao, Xu Wang, Huiling Guo, Hui Hui Sun, Xiao Ying Lai, Li Ying Liu, Mingxia Zhu, Hao Yan Wang, Yi Fan Li, Li Yang Yu, Changchuan Xie, Hong Rui Wang, Wei Mo, Hai Meng Zhou, Shuai Chen, Guosheng Liang, Tong Jin Zhao

Research output: Contribution to journalArticlepeer-review

74 Scopus citations


Fatty acid uptake is the first step in fatty acid utilization, but it remains unclear how the process is regulated. Protein palmitoylation is a fatty acyl modification that plays a key regulatory role in protein targeting and trafficking; however, its function in regulating fatty acid metabolism is unknown. Here, we show that two of the Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases, DHHC4 and DHHC5, regulate fatty acid uptake. DHHC4 and DHHC5 function at different subcellular localizations to control the palmitoylation, plasma membrane localization, and fatty acid uptake activity of the scavenger receptor CD36. Depletion of either DHHC4 or DHHC5 in cells disrupts CD36-dependent fatty acid uptake. Furthermore, both Dhhc4 −/− and adipose-specific Dhhc5 knockout mice show decreased fatty acid uptake activity in adipose tissues and develop severe hypothermia upon acute cold exposure. These findings demonstrate a critical role of DHHC4 and DHHC5 in regulating fatty acid uptake.

Original languageEnglish (US)
Pages (from-to)209-221.e5
JournalCell Reports
Issue number1
StatePublished - Jan 2 2019


  • CD36
  • DHHC4
  • DHHC5
  • fatty acid uptake
  • protein palmitoylation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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