Chronic succinate exposure does not cause liver injury

Patients with metabolic syndrome and liver dysfunction demonstrate elevated levels of succinate in the circulation. Succinate has been causally associated with nonalcoholic fatty liver disease (NAFLD) in multiple animal models and via different mechanisms including interaction with succinate receptor-1 (SUCNR-1) in hepatic stellate cells (HSCs), activity of AMP-activated protein kinase (AMPK) and others. Although skeletal muscle is a major source of endogenous succinate, here, using a transgenic mouse with muscle-specific ablation of succinate dehydrogenase complex subunit C (SDHC knockout animal), we show that sustained, long-term endogenous elevation of blood succinate does not cause liver injury. Both macroscopically and histologically, livers from transgenic animals appear similar to wild-type counterparts. Moreover, tests for liver function and other biochemical serum surrogates of organ integrity, and measurements of oxygen consumption by high resolution respirometry, do not indicate evidence of succinate-induced liver toxicity in transgenic animals. This data suggests that chronically elevated endogenous succinate causes no conspicuous evidence of liver dysfunction at histological, biochemical, or metabolic levels.NEW & NOTEWORTHY Succinate has been associated with hepatotoxicity in cellular, animal, and human models, including metabolic syndrome. This is the first report that evaluates the liver integrity effect of chronically elevated systemic succinate as measured by mass spectrometry. We show that liver histopathology, functional readouts, and high-resolution respirometry show normal levels following chronic succinate exposure. Thus, this research challenges the prevalent concept that succinate elevation is injurious to the liver in vivo.