Lp(a) and the Risk for Cardiovascular Disease: Focus on the Lp(a) Paradox in Diabetes Mellitus

Abstract

Lipoprotein(a) (Lp(a)) is one of the strongest causal risk factors of atherosclerotic disease. It is rich in cholesteryl ester and composed of apolipoprotein B and apo(a). Plasma Lp(a) levels are determined by apo(a) transcriptional activity driven by a direct repeat (DR) response element in the apo(a) promoter under the control of (HNF)4α Farnesoid-X receptor (FXR) ligands play a key role in the downregulation of APOA expression. In vitro studies on the catabolism of Lp(a) have revealed that Lp(a) binds to several specific lipoprotein receptors; however, their in vivo role remains elusive. There are more than 1000 publications on the role of diabetes mellitus (DM) in Lp(a) metabolism; however, the data is often inconsistent and confusing. In patients suffering from Type-I diabetes mellitus (T1DM), provided they are metabolically well-controlled, Lp(a) plasma concentrations are directly comparable to healthy individuals. In contrast, there exists a paradox in T2DM patients, as many of these patients have reduced Lp(a) levels; however, they are still at an increased cardiovascular risk. The Lp(a) lowering mechanism observed in T2DM patients is most probably caused by mutations in the mature-onset diabetes of the young (MODY) gene and possibly other polymorphisms in key transcription factors of the apolipoprotein (a) gene (APOA).

Association between lipoprotein(a) and peripheral arterial disease in coronary artery bypass grafting patients

“…Our result indicated that the correlation between LP(a) serum level and PAD severity was not observed in patients with DM history. Surprisingly, researchers have proposed that DM patients always have reduced Lp(a) levels 28 . We speculated that the existence of DM might have some influence on the function of LP(a), thus concealing the relation between LP(a) serum level and PAD.…”

Glucose metabolism status modifies the relationship between lipoprotein(a) and carotid plaques in individuals with fatty liver disease

“…The recent studies indicated that higher Lp(a) level was associated with subclinical coronary atherosclerosis in asymptomatic subjects ( 42 ), and elevated baseline Lp(a) was associated with subclinical vascular and valvular calcification in the White and Black participants ( 43 ). It is known that Lp(a) and its associated oxidized phospholipids could induce a proinflammatory response, causing cellular apoptosis and necrosis which accelerate necrotic core formation ( 44 , 45 ). Furthermore, Lp(a) contains proatherogenic components of LDL, and its prothrombotic effects through the plasminogen-like apolipoprotein(a) also contribute to the atherosclerosis ( 46 , 47 ).…”

The 10 essential questions regarding lipoprotein(a)

“…Although there are conflicting data published, the majority of studies found that individuals suffering from type-2 diabetes mellitus (T2DM) or metabolic syndrome indeed exhibit lower plasma Lp(a) as compared with healthy controls [47]. We recently reviewed this topic in more detail and came to the following conclusions [48]:…”

“…There remains still a large fraction of patients with T2DM exhibiting reduced levels of Lp(a) in whom mutations in transcription factors have not yet documented. Part of them might relate to altered metabolism of triglyceride-rich lipoproteins as suggest by Skoumas et al [47], yet there remain still numerous questions with respect to the pathophysiology of the ‘Lp(a) paradox in diabetes mellitus’ [48].…”

“…Although there are conflicting data published, the majority of studies found that individuals suffering from type-2 diabetes mellitus (T2DM) or metabolic syndrome indeed exhibit lower plasma Lp(a) as compared with healthy controls [47]. We recently reviewed this topic in more detail and came to the following conclusions [48]: FIGURE 1. 3a,6a,7a,12a-Tetrahydroxy-5b-cholan-24-oic acid is a tetrahydroxylated bile acid and thus much better water soluble than the conventional bile acids.…”