University of São Paulo: Advances understanding of fatty liver, a disease still untreated

Liver steatosis, popularly known as fatty liver, is characterized by an excess of fat in the liver, an organ responsible mainly for the metabolism of nutrients. According to the Brazilian Society of Hepatology, this is the most frequent liver disease today, although there is still no treatment other than avoiding risk factors such as obesity.

In seeking to understand the molecular mechanisms of metabolism of this condition, researchers from the Institute of Chemistry (IQ) at USP described – at the molecular level – what happens at the beginning of the disease, and revealed that mitochondria, cell organelles with a central role in the metabolism of molecules fat (lipids), behave differently from what was thought up until then: even if fragmented, they do not cease to perform their function. “Understanding the involvement of molecules is essential to progress in the development of disease treatment, this brings new ideas on how to develop new drugs”, says Alicia Kowaltowski, a professor at the IQ who supervised Pamela Kakimoto’s doctoral research.

The accumulation of lipids in liver cells, called hepatocytes, compromises the proper functioning of the organ, whose main function is to metabolize, that is, to make the nutrients ingested in food different molecules and, therefore, capable of being used by the body. The common causes of this disorder are excessive alcohol consumption and scenarios linked to diabetes, overweight, physical inactivity and poor diet, when it is called Non-Alcoholic Fatty Liver Disease (NAFLD), which affects up to 30% of the global population, being the focus of the study. According to researcher Pamela, fatty liver (steatosis) can progress to steatohepatitis, defined by inflammation, which, in turn, has a risk of becoming cirrhosis, with the loss of organ function, and reach a more advanced stage, the cancer. The disease, which is difficult to diagnose, tends to be silent. “With the lack of pharmacological treatment, the concern is that more and more patients need transplants, as this is a disease linked to obesity, which is growing in the population”, he adds.

What metabolic mechanisms are involved in fatty liver?
The research was supported by the Research Center on Redox Processes in Biomedicine (Redoxoma) and the Foundation for Research Support of the State of São Paulo (Fapesp) and the collaboration of Professor Antonio Zorzano, at the Biomedical Research Institute of Barcelona, ​​Spain. The article entitled Increased glycolysis is an early consequence of palmitate lipotoxicity mediated by redox signaling was published this month on the Science Direct platform.

The researchers sought to analyze the metabolic mechanisms involved in the onset of changes caused by these droplets of fat in hepatocytes, before the more advanced stages of the disease. The emphasis was given to mitochondria, central organelles in the liver’s metabolism, which act in the degradation of lipids and in the production of a form of energy assimilable to the body, adenosine triphosphate, known as ATP. To do this, the scientists simulated the condition of fatty liver in an in vitro model, by using hepatocytes and overloading them with palmitate, a fatty acid, resembling the scenario of excess fat in tissue. Within a six-hour period of stimulation, the mitochondria were fragmented, as well as the network that interconnects them in the cell, and adopted a round shape, rather than the characteristic flat shape, similar to a bean seed.

According to Pamela, until then, in biology, it was believed that the morphology of mitochondria was essentially linked to its function and, therefore, its fragmentation and shape change would compromise its functioning, but this was not what the results revealed. By the parameters evaluated, the production of ATP did not change, that is, the mitochondria function remained at normal levels. “This is unprecedented and surprising: even though the mitochondria were fragmented, they were working very well”, adds Alicia.

In contrast, the production of ATP outside the mitochondria, which is a secondary form of energy production, has increased, a surprising result. “Usually, when one decreases, the other increases and vice versa. But, in this case, mitochondrial production was maintained and outside production increased”, says Pâmela.

“Without basic science, no progress is made”
In addition to providing energy for cells, mitochondria act in the regulation of free radicals, which are derived from this cellular respiration process and can lead to aging and cell death. The study identified that mitochondrial free radicals (oxidants) are involved in signaling and regulating glucose metabolism outside the mitochondria, a relationship also not expected due to the classic separation between glucose metabolism, which is a carbohydrate, and lipid, which is fat , in the cells.

Through laboratory manipulations with living cells, the researchers showed that the level of toxicity generated by excess lipids alters the balance between oxidants and antioxidants and this, in turn, interferes with glucose degradation. When the production of oxidants in the mitochondria is reduced and increased, the production of glycolytic ATP is altered: “The results show a mechanism of glucose regulation that has never been described before”, says Alicia.

The study advances the understanding of metabolic regulation in the body, including metabolic syndrome, which describes a set of health risk factors related to the accumulation of lipids and glucose, from diabetes to cardiovascular disease and fatty liver disease itself. The researcher Alicia emphasizes that, only by understanding the molecular mechanism, a basis is formed to, in the future, contribute to the development of medicines. “Without basic science, there is no progress”, he says.

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