2. Academic Validation
  3. Non-catalytic mechanisms of KMT5C regulating hepatic gluconeogenesis

Non-catalytic mechanisms of KMT5C regulating hepatic gluconeogenesis

  • Nat Commun. 2025 Feb 10;16(1):1483. doi: 10.1038/s41467-025-56696-y.
Qingwen Zhao 1 2,  Xuan Cui 1,  Qi Zhu 1,  Feiyan Li 1,  Ran Bao 3,  Ting Shi 1,  Haojie Liu 1,  Wenjing Lv 1,  Yingjiang Xu 4,  Yue Gao 2,  Qi-Qun Tang 1,  Min Zhang 5,  Dongning Pan 6 7
Affiliations

Affiliations

  • 1 Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 2 Zhejiang Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Senile Chronic Diseases, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China.
  • 3 Department of Cardiovascular Medicine, Dandong Central Hospital, Dandong, Liaoning, China.
  • 4 Department of Interventional Vascular Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, China.
  • 5 Department of Endocrinology and Metabolism, Qingpu Branch of Zhongshan Hospital affiliated to Fudan University, Shanghai, China. zhangmin132226@126.com.
  • 6 Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, Shanghai, China. dongning.pan@fudan.edu.cn.
  • 7 Department of Endocrinology and Metabolism, Qingpu Branch of Zhongshan Hospital affiliated to Fudan University, Shanghai, China. dongning.pan@fudan.edu.cn.
PMID: 39929827 DOI: 10.1038/s41467-025-56696-y
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.

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