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Lipids versus hepatic inflammation: a lysosomal interplay

The consumption of a healthy diet in combination with regular physical exercise is essential for an optimal and healthy condition, keeping the body in good shape. Although dietary guidelines may help in defining what is a healthy diet, the term healthy not only depends on individual needs and/or opinions.

It can also be influenced by factors such as genetics, gender, age, cultural habits, nutrient availability and socioeconomic state. Indeed, it is evident that continuous malnutrition has contributed to the global increase in the incidence of the Metabolic Syndrome (MetS) and metabolic comorbidities, including type 2 diabetes, cardiovascular disease and non-alcoholic fatty liver disease (NAFLD).

Upon eating fat-enriched foods, excess lipids will be transported to and taken up by the liver. Hence, the more fat we eat, the more lipids will accumulate inside hepatic cells. This common, reversible condition is also known as steatosis, which is present in approximately 10-25 percent of the general population and is observed in 80 percent of the obese population. However, if it doesn’t have a timely diagnosis, simple fat accumulation in the liver can further progress to irreversible hepatic inflammation (NASH), which may lead to severe liver damage including fibrosis, cirrhosis or liver failure. Currently, the gold standard to diagnose NASH is by means of an invasive liver biopsy and given the fact that therapeutic options to cure NASH do not exist, NASH is considered a major health threat.

The liver encompasses a variety of cells, including resident macrophages referred to as Kupffer cells. These cells are known to carry specific lipoprotein receptors on their plasma membrane, which ensure that lipoproteins can be taken up. After initial uptake, lipoproteins will enter the cellular acidic organelles, known as lysosomes, to be further processed into smaller lipid particles. After being transported out of the lysosomes, these lipid particles can be directly used for cellular energy supply, stored in the cytoplasm or transported to the circulation. Nevertheless, in case of overweight and/or obesity, excess amounts of lipoproteins continuously circulate in the bloodstream, which enables them to undergo oxidative modifications, resulting in the formation of so-called oxLDL.

In contrast to native LDL, our group has previously shown that oxLDL gets trapped inside the lysosomes, a phenomenon that is associated with the development of NASH. These data revealed that the location of lipoproteins rather than the accumulation is crucial for triggering an inflammatory response in the liver. In line with these findings, we also found that lysosomal accumulation of oxLDL resulted in lysosomal dysfunction, which caused a leakage of lysosomal enzymes into the circulation.

More specifically, we found that the abundant lysosomal enzyme cathepsin D can be used as a biomarker that distinguishes between NASH and simple steatosis, both in adults and in children. To take this a step further, we used a specific NASH mouse model to investigate the impact of inhibiting lysosomal enzymes on NASH progression. Our results showed significant decreases in both plasma and liver lipid levels as well as improvements in hepatic inflammation. Altogether, our pioneering results opened new venues for earlier detection, better treatment and prevention of NASH and associated metabolic complications.

 

Ronit Shiri-Sverdlov is Professor of Hepatic Inflammation and Metabolic Health at Maastricht University. She will present “Role of lysosomes in NASH” at the Global NASH Congress.

 

The Global NASH Congress will take place in London, February 25th-26th. Download the agenda now to see what will be discussed.

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