The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 11 No.
7 • December 2008
Cysteine Decreases Expression of Genes Involved in Liver Cell Fatty Acid Synthesis
Sterol regulatory element-binding protein (SREBP)-1c has been found to be a key transcription factor for the expression/regulation of lipogenic (fat producing) enzyme genes such as fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase (G6PDH) and stearoyl-coenzyme A desaturase (SCD) in liver (but not adipocytes) cells. A new cell culture study shows that the amino acid L-cysteine reduces (down-regulates) SREBP-1c regulated lipogenic enzymes expression in liver cells by increasing glutathione levels in the cells. The study was done using human hepatoma (HepG2) cells that were exposed to various concentrations of L-cysteine.
Oxidative stress has been reported to increase the activity of SREBP-1c in human liver cells. ROS (reactive oxygen species) have also been found to be critical mediators of insulin-dependent lipogenesis. L-cysteine is required for and is usually the limiting amino acid in the synthesis of glutathione, one of the most important endogenous antioxidant defense molecules. In this study, exposure of cells to 5 mM L-cysteine was reported to reduce the mRNA concentration of SREBP-1c (–35 to –43%) and its target genes fatty acid synthase (FAS; –20 to –50%); glucose-6-phosphate-dehydrogenase (G6PDH, –31 to –35%); and stearoyl-coenzyme A desaturase (SCD)1 by –34 to –50%. Moreover, the cells treated with L-cysteine had 47% higher glutathione and 47% lower triglyceride concentrations than control cells. In experiments where cells were treated with both L-cysteine and an inhibitor of glutathione synthesis, no downregulation of the lipogenic genes was seen, showing that the effect was mediated by increased glutathione. Treatment with an oxidant (CuSO4) upregulated the activity of the lipogenic enzymes compared to control cells, but concurrent treatment of L-cysteine with the oxidant caused gene expression to remain at the control level.
As we have mentioned before, both of us take an L-cysteine supplement called Root Food™ (both for its glutathione-synthesis supporting effects and because large amounts of cysteine are required for hair synthesis). We are very happy to learn of this important effect of L-cysteine in helping limit the oxidative stress that increases fat synthesis in the liver. Cysteine is also a limiting nutrient for the liver synthesis of metallothionines, molecules which help to detoxify and excrete heavy metals, many of which are free radical catalyst pro-oxidants.
Another study reported that mice fed with a diet containing fish oils at a level of 10% of energy intake had levels of SREBP-1 protein decreased by 50% (compared to controls) with concomitant reductions of lipogenic enzymes. “These data suggest that physiological doses of fish oil feeding effectively decrease expression of liver lipogenic enzymes by inhibiting SREBP-1 proteolytic cascade . . .”
1. Sekiya et al. SREBP-1-independent regulation of lipogenic gene expression in adipocytes. J Lipid Res 48:1581-91 (2007).
2. Bettzieche et al. L-cysteine down-regulates SREBP-1c-regulated lipogenic enzymes expression via glutathione in HepG2 cells. Ann Nutr Metab 52:196-203 (2008).
3. Sekiya et al. Oxidative stress induced lipid accumulation via SREBP1c activation in HepG2 cells,” Biochem Biophys Res Commun 375:602-7 (2008).
3a. Berniakovich et al. p66Shc-generated oxidative signal promotes fat accumulation. J Biol Chem 283(49):34283-93 (2008).
4. Nakatani et al. A low fish oil inhibits SREBP-1 proteolytic cascade, while a high fish oil feeding decreases SREBP-1 mRNA in mice liver: relationship to anti-obesity. J Lipid Res 44:369-79 (2003).