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Investigators have begun to shed light on the pathophysiology of non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) in regard to branched-chain fatty acids (BCFAs).¹

A team of investigators, led by José Ignacio Martínez-Montoro, Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Instituto de Investigación Biomédica de Málaga (IBIMA), Faculty of Medicine, University of Málaga, evaluated the serum and hepatic profile of branched-chain fatty acids in patients at different stages of NAFLD.

“The pathogenesis of NAFLD is closely associated with metabolic dysfunction; indeed, this entity usually coexists with other metabolic comorbidities, such as obesity, type 2 diabetes mellitus, insulin resistance, dyslipidemia, or hypertension,” the authors wrote. “Although the mechanisms involved in the development and progression of NAFLD are not fully understood, sedentary lifestyle and excessive caloric intake, obesity, insulin resistance, genetic modifiers, and age have been postulated to play an important role.”

Recent Research

Recently, investigators have found the alterations in the hepatic lipidome constitute is a factor along with gut microbiome and related metabolites, involved in the pathophysiology of NAFLD.

In the case-control study, the investigators examined 27 participants without NAFLD, 49 patients with NAFLD, and 17 patients with NASH, defined by liver biopsies. Each patient had severe obesity who underwent bariatric surgery at the Virgen de la Arrixaca University Hospital in Murcia between 2020-2021 between ages of 18-65 years with a body mass index (BMI) of at least 40 kg/m² or 35 kg/m² with significant obesity-related comorbidities, and a duration of obesity of at least 5 years.

Patients were excluded if they had liver diseases other than NAFLD, including viral hepatitis, medication-related disorders, autoimmune disease, hepatocellular carcinoma, hemochromatosis, Wilson's disease, familial/genetic causes, as well as a history of excessive alcohol use, and treatment with any drugs that potentially cause steatosis, including tamoxifen, amiodarone, and valproic acid.

The team analyzed serum hepatic levels of BCFAs by gas chromatography-mass spectrometry, as well as the hepatic expression of genes involved in the endogenous synthesis of BCFAs using real-time quantitative polymerase chain reaction (RT-qPCR).

The Data

The results show a significant increase in hepatic BCFAs in patients with NAFLD compared to participants without NAFLD. However, there no differences found in serum BCFAs between study groups.

They found trimethyl BCFAs, iso-BCFAs, and anteiso-BCFAs increased in patients with either NAFLD or NASH compared to participants without NAFLD.

There was also a relationship between BCFAs and the histopathological diagnosis of NAFLD. The correlation analysis also showed a relationship with other histological and biochemical parameters related to NAFLD or NASH.

The gene expression analysis of the liver showed mRNA levels of BCAT1, BCAT2, and BCKDA were upregulated in patients with NAFLD.

“Despite the fact that we found no differences in the serum profile of BCFAs between the studied groups, we observed a strong positive correlation between the levels of hepatic BCFAs not only with the histopathological diagnosis of NAFLD but also with other histopathological and biochemical parameters associated with NAFLD such as SAF score, hepatocyte ballooning, or the levels of AST and ALT,” the authors wrote. “We have shown for the first time that NAFLD is associated with significantly increased levels of hepatic BCFAs in patients with severe obesity. Also, we have described that this increase is not reflected in serum levels of BCFAs, as we did not find differences among study groups.”

References:

Martínez‐Montoro, J. I., Núñez‐Sánchez, M. Á., Martinez‐Sanchez, M. A., Balaguer‐Román, A., Fernández‐Ruiz, V. E., Ferrer‐Gómez, M., Sledzinski, T., Frutos, M. D., Fernández‐García, J. C., Mika, A., & Ramos‐Molina, B. (2023). Hepatic and serum branched‐chain fatty acid profile in patients with nonalcoholic fatty liver disease: A case–control study. Obesity. https://doi.org/10.1002/oby.23711