Non-alcoholic fatty liver: MSR1 mediates lipid-induced inflammation

NAFLD is a form of fatty liver (steatosis hepatitis) not caused by increased alcohol consumption. The prevalence in Europe is estimated to be between 20 and 30%.

Non-alcoholic fatty liver disease, NAFLD for short, is a form of fatty liver (steatosis hepatitis) that is not caused by increased alcohol consumption. It is the most common chronic liver disease in most industrialized countries. The prevalence in Europe is estimated to be between 20 and 30%.

Key Takeaways:

In a British cohort of 3,700 adults, researchers found non-alcoholic steatosis in one in five subjects. Men with (visceral) obesity appear to be most at risk. High-risk patients with metabolic syndrome are also more likely to suffer from NAFLD. 

A study from the UK, presented during the ILC Digital 2020 by Dr. Olivier Govaere from the Institute of Translational and Clinical Research, Newcastle upon Tyne, UK, shows that the macrophage scavenger receptor-1 (MSR1) appears to have an influence on the development of non-alcoholic fatty liver (NAFLD). Govaere and colleagues had reviewed various studies and human transcriptomic and genetic data, transgenic mouse models, and in vitro assays together suggest a crucial role of MSR1 as a sensor of lipid homeostasis and identified it as a potential therapeutic target in the treatment of NAFLD.

The scavenger receptors of the scavenger pathway are involved in lipid metabolism and the innate immune response. The scavenger receptors are found on macrophages, among other things. Although the less severe chronic inflammation of the liver (steatohepatitis) plays a key role in the pathogenesis of NAFLD, there is considerable variation between patients and the molecular regulators that determine obesity-associated inflammation, and the resulting disease course is not fully defined.

MSR1 expression is associated with higher disease activity

Recent data, Govaere said, now show that proinflammatory activation of macrophages by saturated fatty acids is independent of the Toll-like receptor 4 (TLR4), but the receptor responsible for this is still unknown. The researchers' working hypothesis was that MSR1 could be involved in inflammatory reactions associated with lipid overload during obesity-induced NAFLD. They analyzed different trials on this:

Govaere and colleagues were able to show that MSR1 expression in the liver is associated with greater disease activity in patients with NAFLD and that hepatic lipid-loaded frothy macrophages are present. 

They were also able to show that the mice lacking MSR1 are protected from diet-related metabolic disorders. Mice without MSR1 showed less hepatitis and fibrosis, less circulating fatty acids, hepatic triglyceride levels, and increased lipid storage in the adipocytes.

In addition, MSR1 triggers inflammatory activation of liver macrophages in vivo and in vitro. The researchers also show that MSR1 induces lipid-induced inflammation independently of the lipopolysaccharide. With regard to a genetic predisposition, they identified 4 SNPs at the MSR1 locus with a p-value<5*10-4, with rs41505344. Quantitative analysis of the characteristics of rs41505344 in 430,101 patients enrolled in the British biobank showed a significant correlation with serum triglycerides and ALT levels.

According to Govaere, the data indicated a critical role of MSR1 as a sensor of lipid homeostasis. This could provide a potential therapeutic target for the treatment of NAFLD.

References:
EASL The Digital international Liver Congress, 27 to 29 August 2020 General hepatology, abstract session, 1 to 3 pm, Friday, 28 August

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