Lipoic acid administration prevents nonalcoholic steatosis linked to long-term high-fat feeding by modulating mitochondrial function

Abstract

Nonalcoholic steatosis is an important hepatic complication of obesity linked to mitochondrial dysfunction and insulin resistance. Furthermore, lipoic acid has been reported to have beneficial effects on mitochondrial function. In this study, we analyzed the potential protective effect of lipoic acid supplementation against the development of nonalcoholic steatosis associated with a long-term high-fat diet feeding and the potential mechanism of this effect. Wistar rats were fed on a standard diet (n=10), a high-fat diet (n=10) and a high-fat diet supplemented with lipoic acid (n=10). A group pair-fed to the latter group (n=6) was also included. Lipoic acid prevented hepatic triglyceride accumulation and liver damage in rats fed a high-fat diet (−68%±11.3% vs. obese group) through the modulation of genes involved in lipogenesis and mitochondrial β-oxidation and by improving insulin sensitivity. Moreover, this molecule showed an inhibitory action on electron transport chain complexes activities (P<.01–P<.001) and adenosine triphosphate synthesis (P<.05), and reduced significantly energy efficiency. By contrast, lipoic acid induced an increase in mitochondrial copy number and in Ucp2 gene expression (P<.001 vs. obese). In summary, this investigation demonstrated the ability of lipoic acid to prevent nonalcoholic steatosis induced by a high-fat intake. Finally, the novelty and importance of this study are the finding of how lipoic acid modulates some of the mitochondrial processes involved in energy homeostasis. The reduction in mitochondrial energy efficiency could also explain, at least in part, the beneficial effects of lipoic acid not only in fatty liver but also in preventing excessive body weight gain.

Introduction

Fatty liver or steatosis refers to a histopathological condition in which an excessive accumulation of lipids, primarily triglycerides (TGs), within hepatocytes occurs [1]. This disease is generally considered as one of the main causes of hepatic dysfunction and an important manifestation of the metabolic syndrome and obesity [2]. Because of the crucial importance of this organ in metabolism and homeostasis, alterations in hepatic function have an impact on the whole organism and could be responsible for several complications derived from the consumption of fat-rich diets, including obesity.

Accumulating evidence indicates that insulin resistance [3] and an impaired mitochondrial function [4], [5] play a central role in the development of nonalcoholic steatosis. In fact, a constellation of mitochondrial abnormalities such as impaired mitochondrial oxidation capacity, significant mitochondrial structural abnormalities, hypertrophy of the microsomal oxidative function, increased activity of the cytochrome P-450 system and generation of free oxygen radicals was described in nonalcoholic steatohepatitis (NASH) livers [6], [7]. In this sense, it is well known that a high-fat diet (HFD) causes alterations in hepatic mitochondrial compartment [8], [9].

α-Lipoic acid (LA) is a natural compound derived from octanoic acid. It is present in a wide variety of plants and animals and synthesized through a reaction catalyzed by lipoic acid synthase within the mitochondria [10]. Also, LA acts as a cofactor of several mitochondrial bioenergetic enzymes [11] and in several processes of aerobic metabolism. Apart from its role in the mitochondria, when supplemented in diets, LA exerts beneficial physiological effects such as attenuation of oxidative stress [12], overcoming of aging decay [13], modulation of glucose metabolism [14], prevention of body weight gain induced by HFD [15], as well as a reduction of energy efficiency [16]. In addition, the ability of LA to reduce serum and tissue lipid levels has been reported by other investigators [17], [18]. Moreover, it has been demonstrated that LA decreases hepatic lipogenesis, although the underlying mechanisms are not completely understood [19].

In light of the above considerations, we suggest that LA treatment may have a protective effect against the development of fatty liver associated with a long-term HFD feeding through the modulation of mitochondrial function and lipid metabolism pathways. To test this hypothesis, we evaluated several parameters of ectopic lipid storage in the liver, mitochondrial function and lipid metabolism in rats fed with HFD supplemented with LA.