Review Tale of two systems: the intertwining duality of fibrinolysis and lipoprotein metabolism, 2023, Dai et al.

[SNT Gatchaman]

Tale of two systems: the intertwining duality of fibrinolysis and lipoprotein metabolism
Wen Dai; Mark Castleberry; Ze Zheng

Fibrinolysis is an enzymatic process that breaks down fibrin clots, while dyslipidemia refers to abnormal levels of lipids and lipoproteins in the blood. Both fibrinolysis and lipoprotein metabolism are critical mechanisms that regulate a myriad of functions in the body, and the imbalance of these mechanisms is linked to the development of pathologic conditions, such as thrombotic complications in atherosclerotic cardiovascular diseases.

Accumulated evidence indicates the close relationship between the 2 seemingly distinct and complicated systems—fibrinolysis and lipoprotein metabolism. Observational studies in humans found that dyslipidemia, characterized by increased blood apoB-lipoprotein and decreased high-density lipoprotein, is associated with lower fibrinolytic potential. Genetic variants of some fibrinolytic regulators are associated with blood lipid levels, supporting a causal relationship between these regulators and lipoprotein metabolism. Mechanistic studies have elucidated many pathways that link the fibrinolytic system and lipoprotein metabolism. Moreover, profibrinolytic therapies improve lipid panels toward an overall cardiometabolic healthier phenotype, while some lipid-lowering treatments increase fibrinolytic potential.

The complex relationship between lipoprotein and fibrinolysis warrants further research to improve our understanding of the bidirectional regulation between the mediators of fibrinolysis and lipoprotein metabolism.


Link | Paywall (Journal of Thrombosis and Haemostasis)

 

[SNT Gatchaman]

Mechanistic studies showed the reciprocal regulation between the fibrinolytic system and lipoprotein metabolism is complicated and multifaceted (Figure 2). However, several major gaps remain and need to be addressed in future studies. For example, varieties of fibrinolytic regulators and their inhibitors are found in circulating lipoproteins. It is unknown how and where the fibrinolytic proteins are incorporated into lipoproteins, and what the biological implication of these associations may play in both fibrinolysis and lipoprotein metabolism.

 

[SNT Gatchaman]

ApoB-100 contains 2 thrombin-cleavable sites at residues 1,297 (β1 domain) and 3,249 (β2 domain). Thrombin, a key enzyme in the coagulation cascade, cleaves apoB-100 and generates truncated fragments of apoB-100. Kringle domains are protein structural domains that are found in a number of proteins involved in blood coagulation and fibrinolysis, including prothrombin, plasminogen and tPA.

There is another type of apoB-lipoprotein found only in humans and certain non-human primates, called lipoprotein (a) (Lp(a)). Lp(a) consists of one copy of apoB-100 and one copy of apolipoprotein (a) (apo(a)), connected by a disulfide bond. The lysine 680 in apoB100 interacts with the lysine binding sites of apo(a) Kringle domain, promoting Lp(a) assembly.

The LPA gene, which encodes for apo(a), evolved from the duplications, deletions, gene conversions, and point mutations of PLG gene encoding for plasminogen. These 2 genes diverged during primate evolution approximately 40 million years ago. Human LPA shares a high sequence homology (78%-100%) with human PLG in both the untranslated and coding regions. PLG consists of 5 distinct paralogous Kringle domains, namely Kringles I-V (KI-KV), each present as single copies, along with one protease domain.

Owing to its shared structure with plasminogen and lack of protease activity, Lp(a) inhibits the fibrinolytic cascade via its ability to bind to and inhibit many of the regulators of the canonical plasminogen activation pathway.

 

[Creekside]

Lots of "complex relationships" in the body, and probably the majority are still unstudied. If ME is the result of one of these feedback loops or other relationships, studying serum samples won't help if we don't know what we're looking for, and maybe ignoring important factors because the textbooks say they're not important.