[MUSIC] Hello, everyone. Welcome back to my Coursera class. This is session four, right, during week seven. So this session is about alcohol, ethanol, right? Alcohol or called ethanol, simple organic compound. So what's the relationship between ethanol consumption and energy metabolism? So in the very beginning, I'm going to introduce how ethanol and alcohol actually is produced. So alcohol is produced from fermentation. We just studied about lactic acid fermentation, right? So this is another major fermentation process done by yeast or some bacteria. Alcohol fermentation and those bacteria and microorganisms can transform sugars like glucose into ethanol, right? And obviously, human beings utilize this alcohol for a long time during the history of our human civilization, right? So this is potting yeast, so again, glucose, fructose, whatever. Those glucose carbohydrates will be degraded throughout the glycolysis. But instead of cellular respiration, they can be transformed into ethanol. So alcohol is a very simple chemical. And once alcohol is consumed and they're metabolically eliminated and the key organ for this alcohol metabolism is liver, liver. So alcohol metabolism involve four types of enzymes. Aldehyde dehydrogenase, alcohol dehydrogenase or CYP2E1 and cytochrome P450, depending on enzymes. So this is the first key event after alcohol consumption. So ethanol coming into the liver in the cytosol. Throughout the alcohol dehydrogenase enzyme action, alcohols will be oxidized into acetaldehyde, right? And this acetaldehyde will be, I mean, from cytosol will be transported into mitochondria. And inside the mitochondria of liver cells, aldehyde dehydrogenase act as electrons and these are the acetaldehyde becomes acetate, okay? This is the primary, the first of biochemical event. And what's the metabolic consequences? So accumulation of NADH, accumulation of NADH. NADH is kind of a reduced electron carrier, and the NADH levels are increased. This is the signal to inhibit gluconeogenesis and inhibit fatty acid oxidation, rather increase fatty acid biosynthesis. So fatty acid biosynthesis is driven by ethanol degradation pathway. So after alcohol consumption inside the liver, fat molecules can be accumulated. This is also called alcoholic fatty liver symptom. Another pathway is CYP2E1 enzyme dependent. So ethanol, I mean, these enzymes and their associated systems localize the smooth endoplasmic reticulum and this catalytic system is microsomal ethanol-oxidizing system. So this ethanol again, being oxidized into acetaldehyde. Interestingly, this enzyme consume NADPH and oxygen, right? And then acetaldehyde again, getting into mitochondria and transformed into acetate and NADPH is produced. So what about this CYP2E1 depend on alcohol dehydrogenase pathway. So overall, many oxygen molecules are involved in this catalytic processes regulated by CYP2E1 and oxygen free radical will be increased which is not good. Because oxygen free radical is indicative of oxidative stress. NADPH molecule will be depleted, because CYP2E1 utilize tons of the NADPH to process ethanol. So in that case, NADPH reduction aggravates oxidative stress. I'm going to explain the reason why NADPH can promote oxidatively stressful condition inside the cell. And ultimately, like previous metabolic pathways, or this CYP2E1 pathways, alcohol consumption, acetate levels will be increased, right? And acetyl-CoA level will be increased subsequently. So that means accumulation of acetyl-CoA means ketone body generation will be stimulated. So very extreme situation can lead to the release of huge amount of ketone bodies and ketone acidosis can be developed from heavy drinking. And one of the intermediate acetaldehyde level will be increased and this acetaldehyde is very, very reactive on metabolites, can destroy cellular macromolecules, protein and lipids. So cellular damages will be increased. So I'm going to introduce why NADPH reducing power is that important for cellular oxidative stress responses. So glutathione, one example is this one. Glutathione is the most powerful cellular antioxidant inside your cells or types of cells. And these three amino acid-based, glutamate, cysteine and glycine, they are covalently linked. This is the structure of glutathione. So those glutathione molecules, when they are reduced, reduced means the self-hydrate of the middle cysteine amino acid. This reduced glutathione, thiones are utilized to remove peroxide. Glutathione GSH is utilized to remove peroxide back to water. The thing is this SH group is supposed to be reduced to act upon those toxic oxidative stress molecules. So NADPH should be constantly supplied to generate reduced antioxidant glutathione. That's why alcohol consumption and subsequent depletion of NADPH, and finally, GSH glutathione antioxidant cannot be functionally maintained. So ultimately, the target cells, the antioxidant activity capacity will be lowered. So cells will be endangered to the severe oxidative stress. So alcohol consumption in particular, chronic ethanol intake and metabolic processes. As I said, acetate or acetaldehyde and those metabolite will be increased. In some cases, ketone body level increased and NADH is too much increased, right? In that case, hepatic lipogenesis are promoted and fatty acid oxidation will be inhibited. So fat molecules will be accumulated and deposited inside the liver. So fatty liver, alcoholic fatty liver, right? And not accessed NADPH will be depleted throughout the ethanol metabolic processes and lipid or many proteins will be peroxidized. I mean, the oxidative stress overall. Oops, sorry about that. Stress will be overall increased. So cellular components will be damaged. So cells will be injured, right? And in worst case scenario, liver tissues will become fibrotic. So overall, liver failure can be developed. This is the fundamental biochemical processes underlying the alcohol metabolism dependent medical complications.