Innovative Target Therapies Are Able to Block the Inflammation Associated with Dysfunction of the Cholesterol Biosynthesis Pathway

Abstract

Abstract:The cholesterol pathway is an essential biochemical process aimed at the synthesis of bioactive molecules involved in multiple crucial cellular functions. The end products of this pathway are sterols, such as cholesterol, which are essential components of cell membranes, precursors of steroid hormones, bile acids and other molecules such as ubiquinone. Several diseases are caused by defects in this metabolic pathway: the most severe forms of which cause neurological involvement (psychomotor retardation and cerebellar ataxia) as a result of a variety of cellular impairments, including mitochondrial dysfunction. These pathologies are induced by convergent mechanisms in which the mitochondrial unit plays a pivotal role contributing to defective apoptosis, autophagy and mitophagy processes. Unraveling these mechanisms would contribute to the development of effective drug treatments for these disorders. In addition, the development of biochemical models could have a substantial impact on the understanding of the mechanism of action of drugs that act on this pathway in multifactor disorders. In this review we will focus in particular on inhibitors of cholesterol synthesis, mitochondria-targeted drugs and inhibitors of the inflammasome.

The effect of N-stearoylethanolamine on adipocytes free cholesterol content and phospholipid composition in rats with obesity-induced insulin resistance

“…Cholesterol is recognized as the main modulator of cell membranes phospholipid composition. It is also well known that the content of cholesterol may vary under different pathological conditions [23][24][25].…”

The Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases

“…In addition to these forms of “systemic” hypocholesterolemia, there can be “tissue” hypocholesterolemias, such as in patients with inherited defects in cholesterol biosynthesis [97], where circulating cholesterol is normal or slightly low but brain cholesterol can be virtually absent. This is due to the fact that all the cholesterol contained in the brain is the result of an in situ synthesis because the blood-brain barrier does not allow the passage of circulating lipoproteins [98,99,100]. Therefore, when there is a defect in cholesterol biosynthesis and cholesterol synthesis is impaired, intermediate metabolites accumulate in the central nervous system and cause apoptosis, autophagy, and NLRP3-inflammasome activation [97,100,101,102] (Figure 3), leading to neuroinflammation [98,99,103].…”

“…This is due to the fact that all the cholesterol contained in the brain is the result of an in situ synthesis because the blood-brain barrier does not allow the passage of circulating lipoproteins [98,99,100]. Therefore, when there is a defect in cholesterol biosynthesis and cholesterol synthesis is impaired, intermediate metabolites accumulate in the central nervous system and cause apoptosis, autophagy, and NLRP3-inflammasome activation [97,100,101,102] (Figure 3), leading to neuroinflammation [98,99,103]. The damage to the central nervous system presents with psychomotor retardation, developmental delay, structural brain malformations, multiple congenital anomalies, microcephaly, autism and other behavioral disorders [97].…”

Inflammasome and Mitophagy Connection in Health and Disease

“…Although there is increasing evidence of the link between mitophagy and the inflammasome in human health and disease [ 1 , 17 , 121 , 122 , 123 ], few studies have reported the key components through which mitophagy regulates the inflammasome and vice versa. The interrelationship between inflammasome and mitophagy is summarized in Figure 3 .…”

“…In the context of cardiovascular diseases, dysregulation of the cholesterol pathway leads to mitochondrial dysfunction and ROS production, which are related to defective autophagy/mitophagy and further activation of the NLRP3 inflammasome [ 122 ]. Lipid-activated eukaryotic initiation factor 2 α (eIF2α) signaling suppresses Parkin-mediated mitophagy, and reduces mitochondrial damage and inflammasome activation [ 158 ].…”