High-Density Lipoprotein in Metabolic Disorders and Beyond: An Exciting New World Full of Challenges and Opportunities

Abstract

High-density lipoprotein (HDL) is an enigmatic member of the plasma lipid and lipoprotein transport system, best known for its ability to promote the reverse cholesterol efflux and the unloading of excess cholesterol from peripheral tissues. More recently, data in experimental mice and humans suggest that HDL may play important novel roles in other physiological processes associated with various metabolic disorders. Important parameters in the HDL functions are its apolipoprotein and lipid content, further reinforcing the principle that HDL structure defines its functionality. Thus, based on current evidence, low levels of HDL-cholesterol (HDL-C) or dysfunctional HDL particles contribute to the development of metabolic diseases such as morbid obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. Interestingly, low levels of HDL-C and dysfunctional HDL particles are observed in patients with multiple myeloma and other types of cancer. Therefore, adjusting HDL-C levels within the optimal range and improving HDL particle functionality is expected to benefit such pathological conditions. The failure of previous clinical trials testing various HDL-C-raising pharmaceuticals does not preclude a significant role for HDL in the treatment of atherosclerosis and related metabolic disorders. Those trials were designed on the principle of "the more the better", ignoring the U-shape relationship between HDL-C levels and morbidity and mortality. Thus, many of these pharmaceuticals should be retested in appropriately designed clinical trials. Novel gene-editing-based pharmaceuticals aiming at altering the apolipoprotein composition of HDL are expected to revolutionize the treatment strategies, improving the functionality of dysfunctional HDL.

Keywords: NAFLD; adipose tissue; atherosclerosis; gene-editing; high-density lipoprotein; morbid obesity; multiple myeloma; pharmaceuticals; pharmacology; type 2 diabetes mellitus.

Figure 1

Proposed mechanisms involving dysfunctional HDL with type 2 diabetes mellitus (T2DM), obesity, nonalcoholic fatty liver disease (NAFLD), and cancer.

Figure 2

Gene-editing strategies currently available for the cure of genetic and hereditary disorders.

Figure 3

Despite previous speculations that HDL-C levels are irrelevant in clinical practice, current evidence supports that raising low HDL-C levels within the optimal range and improving the functionality of dysfunctional HDL are expected to have significant benefit to the prevention and treatment of multiple metabolic disorders.