VKORC1L1, a paralog of vitamin K oxidoreductase (VKORC1), is a vitamin K epoxide reductase enzyme. It participates in the vitamin K cycle, converting vitamin K epoxide into reduced vitamin K, which serves as a co-factor for γ-carboxylation of proteins like coagulation factors [1,2,3]. It also has a role in maintaining intracellular redox homeostasis [5]. Genetic models, such as mouse models, have been crucial in studying its function.

In Vkorc1-/-; Vkorc1l1-/-double-knockout mice, severe hemorrhaging was observed at birth, indicating that VKORC1L1 supports carboxylation during pre-and perinatal periods. However, only VKORC1 sustains hemostasis beyond postnatal day 7 (P7) [3]. Overexpression of VKORC1L1 in the liver of adult Vkorc1-/-mice rescued carboxylation and hemostasis, further validating its role in supporting vitamin K-dependent protein carboxylation in vivo [3]. Additionally, in a Vkorc1l1 mutant mouse model, the mutants showed a lower fat-to-body-weight ratio, decreased plasma leptin, and underdeveloped white adipose tissue, suggesting that VKORC1L1 promotes adipogenesis [4].

In conclusion, VKORC1L1 is essential for vitamin K-dependent protein carboxylation, especially during the pre-and perinatal periods. Its function in adipogenesis was also demonstrated through mouse models. These findings from KO mouse models contribute to our understanding of its role in physiological processes related to blood coagulation and adipose development [3,4].

References:

1. Lacombe, Julie, Ferron, Mathieu. 2018. VKORC1L1, An Enzyme Mediating the Effect of Vitamin K in Liver and Extrahepatic Tissues. In Nutrients, 10, . doi:10.3390/nu10080970. https://pubmed.ncbi.nlm.nih.gov/30050002/

2. Oldenburg, Johannes, Watzka, Matthias, Bevans, Carville G. 2015. VKORC1 and VKORC1L1: Why do Vertebrates Have Two Vitamin K 2,3-Epoxide Reductases? In Nutrients, 7, 6250-80. doi:10.3390/nu7085280. https://pubmed.ncbi.nlm.nih.gov/26264021/

3. Lacombe, Julie, Rishavy, Mark A, Berkner, Kathleen L, Ferron, Mathieu. 2018. VKOR paralog VKORC1L1 supports vitamin K-dependent protein carboxylation in vivo. In JCI insight, 3, . doi:10.1172/jci.insight.96501. https://pubmed.ncbi.nlm.nih.gov/29321368/

4. Ding, Yi, Cui, Jing, Wang, Qi, Han, Min, Wu, Xiaohui. 2018. The Vitamin K Epoxide Reductase Vkorc1l1 Promotes Preadipocyte Differentiation in Mice. In Obesity (Silver Spring, Md.), 26, 1303-1311. doi:10.1002/oby.22206. https://pubmed.ncbi.nlm.nih.gov/29963761/

5. Czogalla, Katrin J, Liphardt, Kerstin, Höning, Klara, Watzka, Matthias, Oldenburg, Johannes. . VKORC1 and VKORC1L1 have distinctly different oral anticoagulant dose-response characteristics and binding sites. In Blood advances, 2, 691-702. doi:10.1182/bloodadvances.2017006775. https://pubmed.ncbi.nlm.nih.gov/29581108/