A research team led by Prof. LI Yu from the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences (CAS) and collaborators uncovered that ethyl lactate, a main nonethanol ingredient found in distilled liquors, lowers alcoholic hepatosteatosis, inflammation and acute-on-chronic liver injury in alcohol-associated liver disease (ALD). The study was published online in Advanced Science on Dec. 11, 2024.

Increasing global alcohol exposure aggravates worldwide prevalence of ALD, which is a major cause of liver-related morbidity and mortality. Aberrant upregulation of hepatic lipogenesis induced by excessive alcohol consumption is a critical driver for the progression of ALD. Currently, there are no effective approaches available for the treatment of ALD patients. 

The severity of ALD is highly dependent on the amount of alcohol intake. Compared with wine and beer, distilled spirits have higher ethanol content, which increases susceptibility to more ethanol ingestion and ALD pathogenesis. 

Alcoholic beverages are complex mixtures composed of water, ethanol and nonethanol ingredients. Due to the special types of raw materials, fermentation processes and aging processes, distilled spirits produce abundant nonethanol ingredients such as esters, acids, higher alcohols and aldehydes. Among which, the nonethanol ingredients determine the unique quality, taste, flavor and types of alcoholic beverages. However, whether the nonethanol ingredient in alcoholic beverages regulates the pathogenesis of ALD remains largely unknown. 

Using gas chromatography with flame ionization detection (GC-FID) and high-performance liquid chromatography with ultraviolet detection (HPLC-UV), scientists identified 40 chemical compounds in five typical distilled spirits in the world, including Whisky, Brandy, Baijiu, Rum and Vodka. Among the 40 nonethanol compounds discovered, 13 compounds with higher concentrations were defined as main nonethanol ingredients of distilled spirits. 

To investigate the roles of main nonethanol ingredients in regulating pathogenesis of ALD, researchers performed in vivo screening by using the mouse model of chronic-plus-binge ethanol feeding (also known as Gao-Binge). Among these 13 compounds, ethyl lactate ameliorates hepatic steatosis, inflammation and acute-on-chronic liver injury in a dose-dependent manner. 

Mechanistically, ethyl lactate ameliorates hepatic steatosis and acute-on-chronic liver injury in ALD by inducing fibroblast growth factor 21 (FGF21), which inhibits alcohol-induced aberrant activation of mTORC1 and hepatic lipogenesis.

Interestingly, ethyl lactate is widely present not only in alcoholic beverages but also in other fermented foods such as vinegar, bread and sausages, and it is also a recognized food flavoring agent. 

These findings advance the understanding of foodborne small molecule ethyl lactate in regulating the progression of ALD, and may provide a new strategy for the prevention and treatment of ALD as well as obesity-related metabolic disorders.

The proposed model for the nonethanol ingredient ethyl lactate-mediated hepatic FGF21 activation and inhibition of ALD progression. Approaches for the modulation of the foodborne molecule ethyl lactate may provide a unique therapeutic pathway for the treatment of ALD. (Image by Prof. LI Yu’s group) 

Paper link: https://doi.org/10.1002/advs.202409516

Media Contact:
WANG Jin
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: wangjin01@sinh.ac.cn
Web: http://english.sinh.cas.cn/