A Journey to the Center of the Liver

If scientists could shrink themselves to microscopic size and take a journey through the human body – like the submarine crew in the 1966 science fiction classic Fantastic Voyage – one of their first stops would no doubt be the liver. The unique structure of our largest internal organ comprises small, hexagonal functional units called lobules, each carrying out more than 500 functions simultaneously. Studies from the 1970s and 1980s revealed that liver cells divide these many tasks among themselves according to their location within each subunit; however, the technology available at the time provided only a blurred picture of this division of labor.

In a new study published today in Nature, scientists from the Weizmann Institute of Science, together with colleagues at Sheba Medical Center and the Mayo Clinic, present the first genetic atlas of a healthy human liver at a resolution of 2 microns. The findings show that the division of labor in the human liver differs from that of other mammals and is more extensive than previously recognized, helping explain why certain regions of the liver are particularly vulnerable to fatty liver disease.

In recent years, technological advances have made it possible to identify which genes are active in each individual cell while also mapping the cells’ precise spatial positions within the tissue. Still, a comprehensive map of functional division in the human liver remained elusive, largely due to the difficulty of obtaining tissue samples from healthy donors. Researchers in Prof. Shalev Itzkovitz’s group at the Weizmann Institute realized that the solution could come from altruistic living liver donation. Because the liver has a remarkable capacity for regeneration, healthy individuals can donate a substantial portion of their livers to patients in need. With the help of Prof. Ido Nachmany and Prof. Niv Pencovich from the Department of General Surgery and Transplantation at Sheba Medical Center, and Dr. Timucin Taner from the Mayo Clinic in Minnesota, the researchers obtained eight liver samples from healthy donors and constructed a gene expression atlas of the human liver.

“”This efficient system was not designed for a modern diet rich in fats and carbohydrates, which may help explain why we tend to accumulate excess fat in the liver”

“Thousands of genes were found to be active at different levels in liver cells across various locations, pointing to a far more precise and complex internal organization than previously thought,” says Itzkovitz. “Instead of the coarse division into three functional zones that has been accepted for decades, the atlas reveals eight regions with distinct roles. This precise mapping now enables any laboratory worldwide to dive deep into the liver and investigate why different regions are susceptible to different diseases. Metabolic diseases, for example, tend to originate in the center of the lobule, whereas viral and autoimmune inflammations primarily appear at its periphery. Likewise, liver cancer and metastases from other cancers have their preferred locations. The key to understanding these patterns lies in the detailed genetic data we have collected.”

To enable comparison with other species, Itzkovitz’s laboratory also mapped healthy livers in mice, as well as in larger mammals – pigs and cows – whose metabolic rates and lobule sizes are similar to those of humans. In all mammals, blood flows through the lobule from the periphery to the center, supplying oxygen and nutrients to cells along the way. As a result, the periphery is characterized by abundance of resources, while the center experiences relative scarcity. In all the mammals studied except humans, these depleted conditions at the center of the lobule resulted in relatively lower cellular activity. In humans, however, the core of the lobule was found to carry out numerous functions, including synthesizing fats from excess energy, producing glucose from non-carbohydrate sources during fasting, filtering toxins and secreting bile to aid digestion.

Another striking difference between the human liver and those of other mammals concerns glucose storage. The liver functions as the body’s “fuel tank,” efficiently absorbing sugars during meals and releasing them in a controlled manner between meals. The study found that in humans, glucose uptake occurs mainly in the centers of the lobules, rather than at their periphery, unlike in mice.

“This division of labor is both a blessing and a curse,” Itzkovitz explains. “It allows the liver to store carbohydrates efficiently: Cells at the center of the lobule absorb and store glucose directly from the blood, while cells at the periphery convert lactate into glucose, further contributing to the energy reserves used during fasting. However, this efficient system was not designed for a modern diet rich in fats and carbohydrates, which may help explain why we tend to accumulate excess fat in the liver and develop liver fibrosis.”

To cope with cellular wear and tear and prevent disease, a unique turnover mechanism appears to have evolved in the center of the human liver lobule. “We found that in humans, unlike in other mammals, a particular type of immune cell prefers to reside in the core of the lobule rather than guarding its periphery – the entry point of blood into the tissue,” says Dr. Oran Yakubovsky of Itzkovitz’s lab, who led the study and is also a surgical resident at Sheba Medical Center. “Kupffer cells are specialized scavenger cells that can offer protection against infections but also engulf, break down and recycle the remains of worn-out cells. We hypothesize that in humans they ‘relocated’ to the center to cope with the increased cellular attrition occurring there.”

In the final part of the study, the scientists demonstrated how their new atlas can be used to trace disease development. They focused on fatty liver disease associated with metabolic dysfunction – a common condition, linked to obesity and diabetes, in which fat accumulates in the liver and may lead to inflammation and fibrosis. Comparing healthy liver cells with those that had begun to accumulate fat revealed a protective response: Cells that started to “gain weight” switched off genes involved in fat production and uptake while activating genes associated with fat breakdown. However, the human liver has a limitation that reduces the efficiency of this process: Fat accumulation also leads to decreased production of certain components of the mitochondria, the organelles responsible for breaking down fats.

“Based on the precise mapping of the liver, it may become possible to develop treatments that will target the genes responsible for making specific regions particularly vulnerable to certain diseases,” says Itzkovitz. “Moreover, the approach of constructing a single-cell–resolution genetic atlas from healthy donor samples can be applied to other organs that have not yet been accurately mapped in humans. It could fundamentally change how we understand the structure and function of the human body.”