Exploring the Role of Carbohydrate and Lipid Metabolism in Multiple Sclerosis

Multiple sclerosis (MS) is a complex immune-mediated neurodegenerative disease characterized by inflammation and demyelination in the central nervous system (CNS). The precise etiology and pathogenesis of MS remain unclear, but a range of metabolic changes, particularly in carbohydrate and lipid metabolism, play a significant role. This blog post delves into the intricate relationship between these metabolic pathways and MS, highlighting potential clinical implications for diagnosis, prognosis, and therapy.

MS involves various metabolic abnormalities that can lead to cellular damage and oxidative stress. These changes are observable through altered levels of related metabolites in the blood and cerebrospinal fluid (CSF) of MS patients. Understanding these metabolic alterations can aid in discovering new diagnostic and prognostic markers and developing therapeutic strategies.

Carbohydrate Metabolism in MS
Glycolysis and TCA Cycle:
Glycolysis involves the breakdown of glucose into pyruvate, which is further processed in the TCA cycle to produce ATP. Studies have shown that the activity of glycolytic enzymes like aldolase C and lactate dehydrogenase (LDH) isoenzymes is altered in MS patients. Increased levels of lactate and NADH in the serum and CSF indicate enhanced glycolytic activity in MS. The TCA cycle's enzyme activity may vary, with decreased levels of succinate dehydrogenase (SD) and alpha-ketoglutarate dehydrogenase (α-KG) observed in MS muscles and brain, respectively, contributing to muscle fatigue and decreased energy production.

Electron Transport Chain (ETC):
The ETC is crucial for ATP production. MS patients show decreased activity of ETC complexes, particularly complexes I, III, and IV, along with cytochrome C (Cyt C). Genetic variations in mitochondrial genes may explain these changes, leading to reduced ATP production and increased susceptibility to MS due to elevated ROS and mitochondrial DNA damage.

Pentose Phosphate Pathway (PPP):
The PPP generates NADPH and pentoses, essential for reducing oxidative stress and supporting cellular functions. MS patients exhibit increased NADPH/NADP ratios and decreased activity of PPP-related enzymes like glutathione peroxidase (GSH-Px). The presence of autoantibodies against transketolase (TK) in MS patients further underscores the pathway's role in disease pathogenesis.

Lipid Metabolism in MS
Pentose Phosphate Pathway (PPP):

Eicosanoid metabolism, liver lipoprotein production, and cellular receptor expression in blood, CNS, and CSF of MS patients, highlighting effects on the myelin sheath. (Pashaei, S., et. al. (2021))

Fatty Acid Oxidation (FAO):
FAO is the primary pathway for fatty acid catabolism, providing significant energy for cells. The rate-limiting enzyme of FAO, carnitine palmitoyltransferase 1 (CPT-1), has multiple isoforms, with CPT-1a being crucial for CNS function. Inhibiting FAO through CPT-1 blockade can reduce neuroinflammation in MS.

Ketone Bodies (KBs):
KBs, produced from acetyl-CoA, serve as alternative fuel sources during fasting. KBs like beta-hydroxybutyrate (BHB) have neuroprotective effects, restoring ETC complex I activity and enhancing energy levels in damaged brain regions of MS patients. Caloric restriction has been shown to elevate KB levels, potentially improving MS symptoms.

Eicosanoids:
Eicosanoids, including prostaglandins (PGs) and leukotrienes (LTs), are inflammatory mediators derived from fatty acids. MS patients exhibit altered levels of eicosanoids and related enzymes, such as cyclooxygenase (COX) and lipoxygenase (LO), highlighting their role in regulating inflammation and T cell function.

Lipoproteins and Cholesterol:
Lipoproteins transport lipids in the bloodstream, with significant changes observed in MS patients. Elevated levels of total cholesterol (TC), cholesterol esters (CE), and low-density lipoprotein cholesterol (LDL-C) are common. Genetic variations in lipoprotein receptors and apolipoproteins (Apo), such as ApoE, influence MS pathogenesis. Statins, which inhibit cholesterol synthesis, may benefit MS treatment by reducing inflammation.

Immune System and Metabolism Crosstalk
Carbohydrate and lipid metabolism significantly impact immune cell functions. Glycolysis and TCA cycle defects can impair T cell proliferation and function. Similarly, altered lipid metabolism, including FAO and eicosanoid pathways, affects immune cell regulation, contributing to MS pathogenesis. Understanding these metabolic-immune interactions can lead to novel therapeutic approaches targeting metabolic pathways to modulate immune responses in MS.

Clinical Applications
Pathological changes in carbohydrate and lipid metabolism offer potential clinical applications in MS. Metabolic alterations can serve as biomarkers for disease diagnosis, prognosis, and therapeutic targets. For instance, elevated lactate and NADH levels, altered enzyme activities, and the presence of specific autoantibodies can help identify disease stages and monitor treatment efficacy.

Conclusion
Research into the metabolic alterations in MS provides valuable insights into the disease's pathogenesis and potential therapeutic strategies. Targeting metabolic pathways may pave the way for innovative treatments, improving patient outcomes. Future studies should also explore the roles of protein and nucleic acid metabolism in MS to develop a comprehensive understanding of the disease's metabolic underpinnings.

References:
Pashaei, S., Mohammadi, P., Yarani, R., Haghgoo, S. M., & Aleagha, M. S. E. (2021). Carbohydrate and lipid metabolism in multiple sclerosis: Clinical implications for etiology, pathogenesis, diagnosis, prognosis, and therapy. Archives of biochemistry and biophysics, 712, 109030.