Metabolic Mash-up
Combining their diverse expertise, LSI researchers are putting a full-court press on metabolic health and disease
When Jiandie Lin opened his lab at the University of Michigan Life Sciences Institute in 2005, he was one of the first metabolism researchers to join the multidisciplinary faculty of cell biologists, geneticists, neurobiologists, chemists and structural biologists. That year, fewer than 100 studies were published about a liver disease that would shape his research program: non-alcoholic steatohepatitis (NASH).
Despite being defined by physicians 25 years earlier, NASH remained fairly unknown and understudied. But Lin foresaw the potential for a pending epidemic due to the disease’s correlation with rising obesity rates. Early on, he set his sights on understanding the cellular environment that defends, or dooms, the body’s largest internal organ.
“It’s not only liver cells that maintain health, but the neighboring cell types that live alongside them,” Lin explains. “They are just as important, and maybe more important in some respects, because different cells constantly communicate with their neighbors, and together they create a functional, healthy tissue.”
Lin’s study of liver disease has expanded as the LSI has grown and evolved, driven in large part by collaborations with faculty members studying different aspects of metabolism, genetics and even biomedical engineering.
Like the diverse cells in the liver’s microenvironment, these scientists have their own unique research functions within the LSI. Yet they connect and communicate with each other — whether through formal collaborations or casual conversations — in ways that create novel advances in the field of metabolic health and disease
As of 2025, NASH — or MASH (metabolic dysfunction-associated steatohepatitis), as it is now called — was the second leading cause of liver transplants among U.S. adults, ahead of hepatitis C and only slightly behind alcohol-associated liver disease. In contrast to the publication output Lin’s first year at the LSI, more than 1,000 new scientific papers referencing MASH or NASH were published in each of the past five years.
The precursor to MASH is found in about one-third of U.S. adults. It results from excess fat buildup in the liver, known as steatosis, which is relatively harmless. But in about one out of five cases, damage caused by persistent steatosis and other metabolic complications sets off a chain reaction leading to inflammation, cell death and eventually end-stage disease such as cirrhosis and cancer.
Lin wanted to understand what caused this switch from steatosis to MASH. He was especially curious about how other cell types in the liver could be influencing liver cells, or hepatocytes. About 60% of the 150 billion cells in a human liver are hepatocytes, and he wondered what was happening with the other 40%. What types of cells were there, and how were they communicating to promote or protect against this harmful chain reaction?
“When we began our liver work, we took a different path, focusing on inter-organ communication and on hormonal signals secreted by one cell type that act on another,” recalls Lin, who is also a professor of cell and developmental biology in the U-M Medical School. A discovery from his lab about 10 years ago brought the role of inter-organ communication in MASH into sharper focus. And it came not from liver tissue but from fat cells, or adipocytes. Lin’s lab revealed that adipocytes in fat tissue were releasing a hormone called NRG4, which seemed to help protect liver health. When NRG4 reaches and interacts with liver cells, it slows the conversion of sugars into lipids and reduces overall fat accumulation in the liver. In mice fed a high-fat diet, animals with higher NRG4 levels show less liver cell death, inflammation and fibrosis. Similar results have been found in human patients, where lower NRG4 correlates with more severe MASH.
“That early work demonstrated that these adipose hormones could have a big impact on liver metabolism and liver disease,” Lin says. “But it also led us to wonder how other cell types in the liver work together to influence hepatocyte health and disease progression.”
To answer that question, Lin’s team turned to an emerging technology that made it possible to analyze the patterns of gene expression in thousands of individual cells at once. Performing single-cell analysis on healthy and diseased livers, the researchers revealed a highdefinition blueprint of the cell types operating in the liver, the signals they produce and receive, and how those signals evolve into distress calls as the disease worsens. “In that study, one of the most interesting changes we observed was in a type of white blood cells called macrophages,” Lin says. “Those findings led to a shift in the lab’s focus to consider how immune cells may be involved with later stages of this disease, like inflammation and cancer. It opened several new research paths for us.”
One of those paths led to a fellow LSI faculty member approaching metabolic health from a vantage point just south of the liver.
Ken Inoki started his scientific career as a practicing physician in Japan, specializing in diabetic kidney disease. There, he saw firsthand the life-threatening impacts of disrupted cell growth.
“In diabetes, the kidney enlarges and also has to filter more blood than a healthy kidney,” explains Inoki, who joined the faculty at the LSI and the U-M Medical School in 2008. “So the cells that form part of this filtration system are forced to grow in size to cover the larger area.”
That enlargement leads to diabetic nephropathy, the most common cause of kidney failure worldwide.
Frustrated by the lack of treatment options for his patients, Inoki turned to the lab bench to see whether he could identify the cellular processes behind the disease conditions. He and his colleagues discovered an essential cellular mechanism that was causing increased cell size in response to growth factors and nutrients in diabetic conditions.
“And that’s how I started studying mTOR,” Inoki recalls.
The mTOR (mechanistic target of rapamycin) pathway serves as a master regulator of cell growth. As a nutrient-sensing protein, mTOR triggers a multitude of cellular processes in response to signals from nutrient and energy sources outside the cell. In diabetic conditions, for example, overabundant nutrients such as glucose and amino acids can overactivate mTOR, leading to the harmful overgrowth of cells in the kidney’s filtration system.
“So that’s why we are continuously working on nutrientsensing mechanisms, to understand this complicated pathway and ways we can prevent its disruption to maintain healthy cells in the kidney,” Inoki says.
During an informal presentation to his fellow LSI faculty members a couple of years ago, Inoki mentioned a protein molecule that he was starting to analyze because it damages kidney cells under diabetic conditions. The name of the molecule, BASP1, immediately caught Lin’s attention. Lin’s single-cell analysis data had found the gene that encodes BASP1 highly expressed in macrophages in both mouse and human MASH livers.
“We had already developed a model and molecular tools for studying what this gene does in the kidneys, and it turned out Jiandie had been hoping to study the had published any of our methods, we were able to share those tools to study the effect of this protein in the progression of MASH.”
The team found that, in mice fed a high-fat diet, macrophages are reprogrammed to produce more BASP1; and switching mice from a high-fat diet to regular food reduced BASP1 levels in the liver. This aberrant increase in BASP1 plays a critical role in the inflammatory responses that drive the transition from steatosis to MASH. Reducing BASP1 levels in mice on a high-fat diet decreased both inflammation and the severity of MASH.
“We know that there is a lot of crosstalk between kidneys and livers, and our labs are also very complementary in terms of Ken’s expertise in biochemical molecular analysis and our work with whole-organism models, so it’s a great combination,” Lin explains. “And it turns out we were able to uncover this very interesting pathway that is influencing the inflammatory response from macrophages, which in turn influences liver disease.”
The BASP1 results provided new understandings of how macrophages participate in the onset and worsening of MASH. But Lin noticed that those same immune cells also seemed to be involved in one of the terminal stages of the disease’s progression: hepatic hepatocellular carcinoma (HCC), the most common form of liver cancer.
“We observed some molecular changes within these macrophages that resembled the tumor microenvironment, but they were happening before any cancer was apparent,” Lin explains. “It almost looked like the liver, once it developed MASH, was already preparing for cancer cells to thrive.”
Now, Lin has teamed up with one of the LSI’s newest faculty members to investigate how these immune cells might be promoting cancer development and whether the hormone his lab discovered almost a decade ago may help reverse course.
From a practical standpoint, the collaboration and proximity to Jiandie’s lab allow us to do experiments that we had not previously envisioned within our own lab.
When Connie Wu joined the LSI faculty in 2023, Lin approached her about a joint project to more accurately measure NRG4 levels in circulation. His lab had recently shown that boosting NRG4 levels could slow down MASH-related HCC in mice. A major challenge in the field had been accurately measuring NRG4 levels in blood, during both disease progression and resolution, and Lin wanted to overcome that barrier to discern what NRG4 might be doing.
“But then I started to wonder if, besides trying to measure NRG4, we could make an mRNA [messenger RNA] therapeutic based on targeting this protein,” Wu recalls. “Our collaboration has expanded from there.”
Wu is a biomedical engineer by training. Her lab develops molecular tools with the dual goals of measuring low-abundance molecules (like the low levels of NRG4 in blood) for earlier disease detection and delivering new therapeutics for disease treatment.
Toward this second goal, Wu and Lin are developing an mRNA-based delivery platform for NRG4. Rather than injecting the purified hormone into mice, the tool would induce the liver to start producing more NRG4 on its own, in a way that is more scalable and refinable. The team is using this approach both to uncover the specific mechanisms of NRG4 in HCC and to pursue new methods for delivering the hormone as a treatment for the cancer.
The collaboration with Lin has also created opportunities to expand her lab’s playbook, developing strategies that she can quickly apply in Lin’s model systems.
“From a practical standpoint, the collaboration and proximity to Jiandie’s lab allow us to do experiments that we had not previously envisioned within our own lab,” explains Wu, who is also an assistant professor of biomedical engineering in the College of Engineering. “But it also helps us scientifically. It gives us a context to focus our technology development efforts toward, and it’s allowed us to extend our applications from cancer to liver disease.”
She isn’t the only LSI faculty member who has added liver disease to their research lineup through connections with Lin’s team.
Partly because we are in this environment where we can connect through faculty talks and trainee presentations, and we knew Jiandie was an expert in this area, we decided to look into what’s happening in the liver. ... I would say my lab is about half liver research now, and I don’t think that would have happened if I wasn’t here at the LSI.
Jun Wu’s collaborations with her fellow LSI researchers predate her role on the faculty, and even the institute itself. As a graduate student at U-M, her first mentor was Ken Inoki, who was at that time a postdoctoral fellow in the same lab where she was completing her first graduate lab rotation.
Five years after Inoki joined the LSI, and after completing her own postdoctoral research at Harvard, Wu was recruited back to U-M in 2013 as an assistant professor. As a new faculty member, she was paired with a faculty mentor at the LSI to help her as she set up her lab. That’s when she first started working with Lin.
Jun Wu founded her lab on the study of a unique type of adipose tissue called thermogenic fat. Rather than storing fat, thermogenic adipocytes help maintain body heat by burning calories and fat stores.
Recently, she noticed a connection between the thermogenic process and liver disease. Her lab had previously discovered that a receptor protein called CHRNA2 can induce the energy-burning process in fat cells. They looked for other areas where this protein might be active, to better understand its various roles throughout the body, and found it was highly expressed in liver cells.
“The liver is tricky, much more complicated than adipose tissue, because a large number of various cell types are present in the tissue niche,” Wu says. “But, partly because we are in this environment where we can connect through faculty talks and trainee presentations, and we knew Jiandie was an expert in this area, we decided to look into what’s happening in the liver.”
Her team found that CHRNA2 sets off a series of cellular programs that protect the liver against the development of MASH. They also found that an FDA-approved drug for treating neurodegeneration could boost CHRNA2 activity in mouse liver.
There are so many types of collaborations that can emerge in an environment like the LSI, whether it’s through common scientific interests, or applying a shared technique, or just chance conversations.
Expanding the field of metabolic research at the LSI, her team is now extending this research into alcohol-associated liver disease. They have found hints indicating that communication between the liver cells and fat tissue can defend against liver damage following alcohol consumption. They are now exploring whether the CHRNA2 pathway may also be a potential drug target for treating alcohol-associated liver disease.
“I would say my lab is about half liver research now, and I don’t think that would have happened if I wasn’t here at the LSI, with Jiandie on the team,” Wu says. “We’ve had tangible collaborations, like publishing papers and submitting grants together. But then there are also very intangible things — our students talk to each other all the time, I go into his office just to talk about the bigger picture of our science. It could be something big or small that leads to a totally new direction.”
“There are so many types of collaborations that can emerge in an environment like the LSI, whether it’s through common scientific interests, or applying a shared technique, or just chance conversations,” Lin adds. “Collaborations like this are hard to predict. They come ad hoc, and then they end up working out really well not just for the labs but for the science.”