Non-catalytic mechanisms of KMT5C regulating hepatic gluconeogenesis

Qingwen Zhao, Xuan Cui, Qi Zhu, Feiyan Li, Ran Bao, Ting Shi, Haojie Liu, Wenjing Lv, Yingjiang Xu, Yue Gao, Qi-Qun Tang, Min Zhang () and Dongning Pan ()
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Qingwen Zhao: Fudan University
Xuan Cui: Fudan University
Qi Zhu: Fudan University
Feiyan Li: Fudan University
Ran Bao: Dandong Central Hospital
Ting Shi: Fudan University
Haojie Liu: Fudan University
Wenjing Lv: Fudan University
Yingjiang Xu: Binzhou Medical University Hospital
Yue Gao: Westlake University
Qi-Qun Tang: Fudan University
Min Zhang: Qingpu Branch of Zhongshan Hospital affiliated to Fudan University
Dongning Pan: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Lysine methyltransferase KMT5C catalyzes deposition of trimethylation on histone H4 lysine 20 (H4K20me3), an epigenetic marker usually associated with gene repression and maintenance of heterochromatin. KMT5C is widely expressed in a variety of tissues, however, its functional role in liver has not been explored. Here, we show Kmt5c is a fasting- and glucagon-induced gene in liver which regulates hepatic gluconeogenesis. Loss of KMT5C in hepatocytes results in downregulated gluconeogenic gene expression and compromised glucose output during fasting. KMT5C fosters gluconeogenesis through decreasing ubiquitination-mediated PGC-1α degradation, which is unexpectedly independent of its methyltransferase activity. In fact, KMT5C impedes the E3 ligase RNF34 binding to the C-terminal of PGC-1α and subsequent ubiquitination-associated degradation. The diabetic mice models and patients show elevated KMT5C levels in the livers, and KMT5C knockdown beneficially reduces gluconeogenesis and fasting blood glucose levels. In conclusion, the present study identifies KMT5C as a hepatic gluconeogenesis regulator by affecting PGC-1α stability.

Date: 2025
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DOI: 10.1038/s41467-025-56696-y

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