Nrf2 Signaling Pathway as a Key to Treatment for Diabetic Dyslipidemia and Atherosclerosis

Abstract

Diabetes mellitus (DM) is a chronic endocrine disorder that affects more than 20 million people in the United States. DM-related complications affect multiple organ systems and are a significant cause of morbidity and mortality among people with DM. Of the numerous acute and chronic complications, atherosclerosis due to diabetic dyslipidemia is a condition that can lead to many life-threatening diseases, such as stroke, coronary artery disease, and myocardial infarction. The nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway is an emerging antioxidative pathway and a promising target for the treatment of DM and its complications. This review aims to explore the Nrf2 pathway's role in combating diabetic dyslipidemia. We will explore risk factors for diabetic dyslipidemia at a cellular level and aim to elucidate how the Nrf2 pathway becomes a potential therapeutic target for DM-related atherosclerosis.

Keywords: Nrf2 pathway; antioxidant; atherosclerosis; diabetes mellitus; dyslipidemia; oxidative stress.

Figure 1

Graphical abstract summarizing the general flow of the development of DM-induced atherosclerotic cardiovascular diseases, with and without the Nrf2 pathway activation: Nrf2, nuclear erythroid 2-related factor 2.

Figure 2

Antioxidative roles of Nrf2 in DM-induced oxidative stress and atherosclerotic progression viewed at the molecular level: Keap1, Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1; Nrf2, nuclear erythroid 2-related factor 2; ARE, antioxidant response element; NQO1, NAD(P)H:quinone oxidoreductase 1; Trx, thioredoxin; HO-1, heme oxygenase 1; DM, diabetes mellitus.

Figure 3

Overall mechanisms of the development of the highlighted risk factors and atherosclerosis in DM environment: HL, hepatic lipase; HSL, hormone-sensitive lipase; LPL, lipoprotein lipase; sdLDL, small dense low-density lipoprotein; VLDL, very-low-density lipoprotein; LSR, lipolysis-stimulated lipoprotein receptor; oxLDL, oxidized low-density lipoprotein; ox-sdLDL, oxidized small dense low-density lipoprotein; LOX-1, lectin-like oxidized LDL receptor-1.

Figure 4

Overall mechanisms of plaque accumulation and inflammation of arterial walls caused by increased atherosclerotic lipoproteins: sdLDL, small dense low-density lipoprotein; ox-sdLDL, oxidized small dense low-density lipoprotein; oxLDL, oxidized low-density lipoprotein; VLDL, very-low-density lipoprotein; LOX-1, lectin-like oxidized LDL receptor-1; VLDLR, very-low-density lipoprotein.