Towards a Healthy Liver

By Dr. Savneet Kaur

Sitting in the upper right-hand side of the abdominal cavity, beneath the diaphragm, is the largest internal organ of our body, ‘the liver.’ Despite being involved in more than 500 vital functions, including metabolism, energy homeostasis, bile synthesis, detoxification, and synthesis, it often remains an overlooked and neglected organ. In this 3-part scientific series, you will learn about how the liver connects with other organs, why liver health is essential for our overall well-being, and how to maintain our liver by observing a healthy lifestyle.

Part 1- Not All Sugars are Sweet for the Liver!

Glucose is a precious fuel and the primary energy source of our body. So have you ever wondered why sweetened beverages and soft drinks are considered unhealthy? Most of these drinks are sweetened with sugars such as sucrose or high fructose corn syrup, containing ∼50–55% fructose. Like glucose, fructose is a simple monosaccharide sugar or carbohydrate with the same molecular formula (C6H12O6) and is mainly found in fruits and vegetables like beets, corn, and potatoes. Glucose is derived from rice, bread, pasta & starchy vegetables like potatoes, peas, corn, zucchini, etc. The table sugar or sucrose contains both glucose and fructose in an exact 50/50 ratio. Both glucose and fructose provide a similar amount of 4 kcal/g calories. Then why is fructose harmful? Let’s first understand what the differences between these two simple sugars are. In terms of glycemic index, a scale from zero to 100 indicates how quickly a carbohydrate increases a person’s blood sugar levels, and glucose has a higher index of 100 while fructose has 23. This means that although glucose is rapidly absorbed in the blood, fructose is digested and absorbed relatively slowly. Now since glucose is rapidly absorbed, it also quickly raises the blood sugar levels and stimulates insulin production, whereas fructose has a negligible impact on circulating insulin levels. High blood insulin quickly elevates levels of a satiety hormone, leptin. At the same time, after a glucose-rich meal, we feel glutted, while consumption of fructose-rich foods leaves us still hungry and craving, thus contributing to overeating. Another significant difference between glucose and fructose is that excess fructose is converted to fatty acids in the liver faster than glucose. Increased fructose consumption (up to 60% of daily calories derived from fructose) results in a high lipid accumulation in the liver (fatty liver) and elevated plasma triglyceride levels.

“high amounts of fructose consumed in soft drinks and soda profoundly harm our gut-liver axis.“

Many new studies have also proposed that high fructose consumption causes several significant pathological changes in the intestine along with the liver. Increased de novo lipogenesis or lipid synthesis may not reflect the detrimental effects of chronic intake of fructose. After ingestion through diet, fructose is taken up into intestinal cells by a specific glucose transporter, GLUT5. Contrary to the earlier notion that fructose is mainly absorbed and cleared by the liver, it has been reported that about 60% of fructose is metabolized in the small intestine only. The metabolized products like glucose and lactate are transported to the liver, with only about 20% intact fructose. However, when we take up fructose in high quantities (≥1 g kg−1), greater than 30% fructose reaches the liver through the portal circulation (a direct blood supply conduit from the intestine to the liver). In the intestine, fructose is known to increase mucosal inflammation significantly, gut microbiota dysbiosis (change in type and amount of commensal bacterial species), leakiness of the gut by disruption of tight junction proteins that maintain the integrity of the intestinal barrier, causing bacterial toxins to enter into the liver through the portal circulation. Endotoxin levels are increased by ∼40% in the portal plasma obtained from mice chronically consuming fructose-sweetened water. In a recent exciting study, the authors have confirmed the contributing role of the leaky gut in fructose-induced fatty liver and inflammation. They demonstrated that mechanistically, a membrane-bound protein, CYP2E1, an oxidase enzyme in the liver that catalyzes the oxidation of a variety of endobiotics and xenobiotics in the liver and intestine, is involved in facilitating the development of inflammation in the liver. Enzyme promotes the generation of reactive oxygen and nitrogen species, cell death, activation of macrophages, and hence metabolic and inflammatory diseases like nonalcoholic steatohepatitis.

In short, the harmful effects of fructose on the liver are mainly governed by its impact on intestinal barrier dysfunction and endotoxemia, once again underscoring the functional linking of the two organs in health and disease. Hence, high amounts of fructose consumed in soft drinks and soda profoundly harm our gut-liver axis. Fruits being nutritionally complex, containing many vitamins, minerals, antioxidants, and fructose, are considered safe. However, people with underlying diabetic conditions should avoid consuming excess fruits.

References

Bray GA. Energy and fructose from beverages sweetened with sugar or high-fructose corn syrup pose a health risk for some people. Adv Nutr. 2013;4(2):220-5.
Kisioglu B, Nergiz-Unal R. Potential effect of maternal dietary sucrose or fructose syrup on CD36, leptin, and ghrelin-mediated fetal programming of obesity. Nutr Neurosci. 2020;23(3):210-220.
Softic S, Gupta MK, Wang GX, Fujisaka S, O’Neill BT, Rao TN, Willoughby J, Harbison C, Fitzgerald K, Ilkayeva O, Newgard CB, Cohen DE, Kahn CR. Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. J Clin Invest. 2017;127(11):4059-4074.
Sellmann C, Priebs J, Landmann M, Degen C, Engstler AJ, Jin CJ, Gärttner S, Spruss A, Huber O, Bergheim I. Diets rich in fructose, fat or fructose and fat alter intestinal barrier function and lead to the development of nonalcoholic fatty liver disease over time. J Nutr Biochem. 2015;26(11):1183-92.
Cho YE, Kim DK, Seo W, Gao B, Yoo SH, Song BJ. Fructose Promotes Leaky Gut, Endotoxemia, and Liver Fibrosis Through Ethanol-Inducible Cytochrome P450-2E1-Mediated Oxidative and Nitrative Stress. Hepatology. 2021;73(6):2180-2195.

About author

Dr. Savneet Kaur pursued Ph.D. from IGIB, Delhi, and DBT-postdoctoral fellowship from SCTIMST, Kerala. Currently, she is an Assistant Professor in the ‘Institute of Liver and Biliary Sciences (ILBS),’ New Delhi. Her research in ILBS revolves around vascular biology of the liver, deciphering cellular and molecular mechanisms underlying liver inflammation and fibrosis. She has significantly contributed to understanding how bone marrow-derived endothelial cells interact with resident liver cells and participate in liver fibrosis. For her work, she has received the prestigious young investigator award from the ‘American Association for the Study of Liver Disease.’ Current efforts of her team are directed towards developing endothelial cell-based targeted therapies for liver diseases. Dr. Savneet is a nominated member of the CPCSEA, Govt of India, and serves as ‘Scientist-in-charge’ of the Animal House Facility in ILBS. Besides the lab, she likes experimenting and innovating in her kitchen.

Edited by: Vikramsingh Gujar