Scientists from the Weizmann Institute, Sheba, and Mayo Clinic have mapped the healthy human liver for the first time at 2-micron resolution, discovering that its division of functions is more complex than in other mammals, explaining why certain areas are particularly susceptible to fatty liver.
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- Eight zones of activity instead of three: the human liver is different from other mammals
- This is how the atlas reveals why certain areas are particularly vulnerable to fatty liver
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If scientists could climb into a microscopic submarine and travel through the body's cells, as in the 1966 film Fantastic Voyage, one of their first stops would be the liver. The unique structure of our body's largest internal organ includes small, hexagonal-shaped units of action called "lobules," each of which performs more than 500 different functions simultaneously. It was already clear in the 70s and 80s that liver cells divide their many roles among themselves according to their location within each subunit, but the technology at the time allowed for only a vague picture of this division. In a new study, published today in the scientific journal Nature, scientists from the Weizmann Institute of Science and their colleagues at Sheba Medical Center and Mayo Clinic present for the first time a genetic atlas of the healthy human liver at a resolution of 2 microns. The findings reveal that the division of functions in the human liver is different from other mammals and more extensive than previously known, and show how it makes certain areas of our liver particularly vulnerable to fatty liver.
First 2-micron resolution look at the human liver
In recent years, technology has been developed that allows us to identify which genes are active in each cell, while also pinpointing the precise spatial location of the cells on a tissue map. However, despite these new capabilities, precise mapping of the distribution of functions in the human liver has been delayed, not least due to the difficulty in obtaining liver samples from healthy individuals. In Prof.'s group Shalev Itzkovich The institute realized that the key to the solution was altruistic liver donations; the liver has a miraculous ability to regenerate, allowing people to donate a large part of it to someone suffering from a disease. Thus, with the help of Prof. Ido Nachmani and Prof. Niv Pankovitz from the Department of General Surgery at Sheba Medical Center and Dr. Timochin Tanner from the Mayo Clinic Transplant Center in Minnesota, the scientists obtained eight samples from healthy donors and compiled an atlas of gene expression in the human liver.
"Thousands of genes were found to be active at different levels in liver cells in different locations, indicating a much more precise and complex internal organization than we had thought," says Prof. Itzkowitz. "Instead of the rough division into three zones of activity, which has been accepted for decades, the atlas revealed eight regions with distinct functions. The precise mapping of the liver now allows any laboratory in the world to delve deep into the liver and investigate why different areas are vulnerable to different diseases. Metabolic diseases, for example, tend to start in the center of the liver, while viral and autoimmune infections appear mainly at its edges. Likewise, liver cancer and metastases from other cancers have their preferred locations. The key to understanding why this is so lies in the precise genetic information we have collected."
In order to compare them to humans, Prof. Itzkovich's laboratory also mapped the healthy liver in mice as well as in larger mammals, pigs and cattle, which have metabolic rates and liver vessel sizes similar to humans. In all mammals, blood flows in the liver from the periphery to the center, providing oxygen and nutrients to the cells. As a result of this pathway, conditions of abundance prevail at the periphery and scarcity in the center. In all mammals examined, except humans, the scarcity conditions in the center of the liver caused the cells there to be relatively less active, while in humans it was discovered that many activities take place in the core of the liver, including the production of excess fats for energy, the synthesis of sugar from non-carbohydrate substances during times of starvation, the filtration of toxins and the production of bile, which aids in digestion.
Another notable difference discovered in the study between the human liver and that of other mammals concerns sugar storage. The liver functions as our body's "fuel tank" by efficiently absorbing the sugars we digest with meals and releasing them in a controlled manner between meals. The study revealed that in humans, glucose absorption is specific to the centers of the vessels, rather than their margins, as in mice.
"This division of labor is both a blessing and a curse," explains Prof. Itzkowitz. "It allows our liver to store carbohydrates efficiently: cells in the center of the liver absorb and store sugar (glucose) directly from the blood, while cells at the edges convert lactate to glucose, thus also contributing to the energy reserves that we use during fasting. However, this efficient division of labor was not designed for the modern diet, which is rich in fats and carbohydrates, and may explain why we tend to accumulate excess fat in the liver and suffer from scarring."
To cope with the erosion and prevent disease, a unique turnover mechanism has evolved in the center of the human liver lobule. "We discovered that in humans, unlike other mammals, one type of immune cell prefers the core of the lobule instead of standing guard at its edge – the gateway for blood to enter the tissue," says Dr. Oren Yakubovsky from Prof. Itzkowitz's lab, who led the study and is also an internist in the General Surgery Unit at Sheba Medical Center. "Kupffer cells are obligate cells that are able to protect against infections but also ingest, break down and recycle the remains of worn-out cells. We hypothesize that they have 'moved to the center' in humans to cope with the increased erosion."
Eight zones of activity instead of three: the human liver is different from other mammals
In the final part of the study, the scientists showed how the new atlas helps track the development of diseases. They focused on metabolic fatty liver disease, a common condition associated with obesity and diabetes, in which fat accumulates in the liver and can lead to inflammation and scarring. Comparing healthy liver cells to cells that have begun to accumulate fat revealed a protective mechanism: cells that have begun to “get fat” turned off genes related to the production and absorption of fat and turned on certain genes related to its breakdown. However, the human liver has a flaw that limits its ability to effectively resist obesity: It turned out that fat accumulation also leads to a decrease in the production of some components in mitochondria – organelles that break down fats.
This is how the atlas reveals why certain areas are particularly vulnerable to fatty liver
"Based on the precise mapping of the liver, it will be possible in the future to develop therapies that target genes that make a particular region particularly vulnerable to a specific disease," says Prof. Itzkowitz. "Moreover, the model of constructing a genetic atlas at single-cell resolution from samples of healthy donors can be applied to other organs that have not yet been accurately mapped in humans, and it may fundamentally change the way we understand the structure and function of the human body."
Also participating in the study were Dr. Keren Behar Halpern, Sapir Shir, Roy Novoselsky, Dr. Adi Egozi, Dr. Tal Barkai, Dr. Yotam Harnik, Dr. Amichai Apriat and Dr. Yael Korem Cohen from the Institute's Department of Molecular Cell Biology; Dr. Chen Meir and Dr. Ron Perry from Sheba Tel Hashomer Medical Center; Dr. Ruben Hoflin from the University of Freiburg, Germany; Ofra Golani, Dr. Ina Goliand, Dr. Yosef Addi, Dr. Meirav Kedmi and Dr. Hadas Keren Shaul from the Institute's Department of Life Sciences Research Infrastructures; and Dr. Liat Plus-Aligor, Yelena Pritchislov and Dana Hirsch from the Institute's Department of Veterinary Resources.
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