Targeting SEMA3A protein could help slow MASLD: Study

Protein seen playing role in liver fat accumulation

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A protein called semaphorin-3A (SEMA3A) may be a key player in the early cellular mechanisms that cause fat to accumulate in the livers of people with metabolic dysfunction-associated steatotic liver disease (MASLD), a study showed.

Experiments in lab-grown human cells and mouse models showed that the protein was elevated in MASLD-associated states like obesity, and led cells that normally export fats out of the liver to have fewer channels to do so. That indicates blocking SEMA3A could be a strategy for slowing MASLD and preventing it from advancing to more serious complications.

The study, “Semaphorin-3A regulates liver sinusoidal endothelial cell porosity and promotes hepatic steatosis,” was published in Nature Cardiovascular Research.

“It may be possible to use the SEMA3A [signaling] molecule we identified to prevent MASLD and its consequences at an early stage,” Eckhard Lammert, PhD, the study’s senior author and a professor at Heinrich Heine University Düsseldorf in Germany, said in a university news story.

“However, we first need to investigate the processes in humans in detail,” added Lammert, who is also the director of the German Diabetes Center’s Institute for Vascular and Islet Cell Biology.

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Early treatment could prevent damage

MASLD, previously known as nonalcoholic fatty liver disease, is characterized by the accumulation of fatty deposits in the liver. Affecting somewhere around a third of people worldwide, it usually doesn’t have any symptoms when it first arises. But over time, a high liver fat content can lead to inflammation and scar tissue that can result in serious and life-threatening liver damage. New treatments that halt MASLD in its early stages could prevent these complications.

Metabolic factors, including obesity and type 2 diabetes, are among the leading risk factors for developing MASLD. Lifestyle changes like eating a healthy diet and exercising regularly are central to managing the condition, but better understanding its molecular underpinnings could help to identify new intervention strategies.

The liver is a key regulator of fat metabolism. It sends excess fatty molecules out into the bloodstream via liver sinusoidal endothelial cells (LSECs). These cells have small pores called fenestrae — Latin for window — that enable the molecules to pass through.

It’s been proposed that a process called defenestration, in which these pores close, could happen early on in the MASLD liver and contribute to disease progression. The idea is that without enough fenestrae, fatty molecules would get stuck in the liver and accumulate there.

Lammert and colleagues in Germany explored the possible role of class 3 semaphorin proteins, which includes SEMA3A, in this process. SEMA3A is found at higher than normal levels in people with obesity, type 2 diabetes, and MASLD.

Results showed that among the seven members of class 3 semaphorins, the Sema3a gene, which codes for SEMA3A, had increased activity in a mouse model of MASLD, characterized by fatty liver, type 2 diabetes, and obesity, as well as in a mouse model of diet-induced obesity.

Lab-grown mouse and human LSECs were found to produce SEMA3A, and exposure to palmitic acid — a saturated fatty molecule found in foods like oil, meat, and dairy products — led to increased SEMA3A gene activity in lab-grown human LSECs.

In addition, exposing lab-grown mouse LSECs to the SEMA3A protein induced defenestration. Overall, this made LSECs less porous, or permeable, to fatty molecules. Likewise, in the MASLD mouse model, where Sema3a gene activity was naturally increased, LSEC’s porosity and fenestrae frequency were diminished with SEMA3A treatment.

Protein contributes to LSEC defenestration

On the other hand, genetically reducing Sema3a gene activity in mice was associated with increased fenestration and porosity. These mice also weighed less, and had reduced liver fat content and lower levels of a liver damage marker than animals with normal SEMA3A levels.

When mice with lower SEMA3A levels were fed a high-fat, obesity-inducing diet, they had less body fat, lower liver fat accumulation, and signs of better fat metabolism than mice given a similar diet but with normal SEMA3A levels.

Similar benefits were seen in mice when the Sema3a gene was deleted specifically in endothelial cells, which would include LSECs. The transport of fatty molecules out of the liver also was increased.

“We conclude that SEMA3A contributes to defenestration of LSECs,” the researchers wrote, noting that it seems to be increased in states associated with MASLD, like obesity or exposure to saturated fats.

Blocking SEMA3A or other proteins it needs to exert its effects could be a possible strategy for slowing down MASLD. Experiments showed that two other proteins, NRP1 and LIMK1, are essential for SEMA3A-mediated defenestration.

“Our study therefore warrants further research on the SEMA3A–NRP1 signaling pathway and its potential targets to attenuate early MASLD development as an entry point for progression to life-threatening … sequelae,” the team concluded.