TY - JOUR

T1 - The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease

AU - Werge, Mikkel Parsberg

AU - McCann, Adrian

AU - Galsgaard, Elisabeth Douglas

AU - Holst, Dorte

AU - Bugge, Anne

AU - Albrechtsen, Nicolai J. Wewer

AU - Gluud, Lise Lotte

PY - 2021

Y1 - 2021

N2 - The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H2S) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD.

AB - The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H2S) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD.

KW - cystathionine beta-synthase/cystathionine gamma-lyase (CBS/CSE) system

KW - glutathione

KW - H2S production

KW - liver fibrosis

KW - non-alcoholic steatohepatitis

KW - sulfur metabolism

U2 - 10.3390/jcm10051081

DO - 10.3390/jcm10051081

M3 - Review

C2 - 33807699

VL - 10

JO - Journal of Clinical Medicine

JF - Journal of Clinical Medicine

SN - 2077-0383

IS - 5

M1 - 1081

ER -