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.
Highlights
The cholesterol pathway (CP), called the mevalonate pathway, is a crucial metabolic process that leads to the synthesis of cholesterol and other biomolecules such as steroidal hormones and isoprenoids
For the synthesis of cholesterol, two molecules of Farnesyl pyrophosphate (FPP) are converted by squalene synthase to the linear hydrocarbon molecule squalene, which is cyclized to the first sterol intermediate, lanosterol, and converted, through a series of reactions, to cholesterol
Recent studies have proven that genetic errors can cause mutations in enzymes involved in the cholesterol cascade [10]; further investigations are necessary to determine the link between mutated enzymes and inflammatory phenotypes, in order to develop new therapies blocking the cholesterol damage in its early stages
Summary
The cholesterol pathway (CP), called the mevalonate pathway, is a crucial metabolic process that leads to the synthesis of cholesterol and other biomolecules such as steroidal hormones and isoprenoids These essential bioactive molecules play an important role in multiple cellular processes, including intracellular signaling, gene expression, protein modification, cell growth/differentiation, cytoskeletal dynamics and stability, mitochondrial function and cell membrane structure [1,2]. The cholesterol pathway is essential for several cell functions The regulation of this biochemical process has been intensely investigated and, in particular, the role of HMGCR which is the rate-controlling enzyme of cholesterol biosynthesis. This enzyme, ubiquitously expressed in all cells, is highly regulated and is controlled by a variety of mechanisms [4]. Recent studies have proven that genetic errors can cause mutations in enzymes involved in the cholesterol cascade [10]; further investigations are necessary to determine the link between mutated enzymes and inflammatory phenotypes, in order to develop new therapies blocking the cholesterol damage in its early stages
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