Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis
Introduction
The global prevalence of non-alcoholic fatty liver disease (NAFLD) is approximately 20–30 % [1]. NAFLD is an umbrella term encompassing the entire spectrum of the disease [2]. Traditionally, NAFLD is divided into non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) [3]. The majority of individuals with NAFLD have NAFL, which is defined as hepatic steatosis (intrahepatic fat ≥5 % of liver weight) in the absence of alternative causal factors such as alcohol, viral infections, or pharmacological agents [4]. NAFL is often regarded as a benign condition given that the majority of individuals with simple steatosis have a low risk for progression to advanced liver disease [5]. In agreement, the accumulation of liver triglycerides, the primary lipid increased in NAFL, is not sufficient to induce hepatocyte dysfunction in experimental models [6], [7]. In contrast to NAFL, NASH is pathological as it is characterized by liver steatosis accompanied by inflammation, hepatocyte damage and/or fibrosis [8], [9], [10]. Currently, 25–30 % of individuals with NAFLD have NASH [8], [9], [10]. It is important to note that NASH is a dynamic disease wherein the defining characteristics may regress to simple steatosis, remain relatively constant, or display progressive advancement of injury, inflammation and fibrosis [11]. Consistent with its progressive characteristics, NASH is a risk factor for developing advanced liver diseases such as cirrhosis and hepatocellular carcinoma (HCC) [12], [13]. In fact, NAFLD is now the second leading indication of liver transplantation and the fastest-growing indication for HCC liver transplantation in the United States [14], [15]. In addition to compromising the well-being of a significant proportion of the population, NAFLD is estimated to be responsible for greater than $100 billion per year in direct medical costs in the United States alone [16]. The significant individual and economic burden is amplified by the fact that there are currently no US Food and Drug Administration-approved pharmacotherapies for NAFLD [17].
The implementation of effective treatments for NAFLD has been challenging due to the complexity of the disease. Genetic variation, age, ethnicity, sex, and co-morbidities all influence NAFLD pathophysiology [2]. Despite the multifactorial nature of this liver disease, a fundamental contributor to NAFLD is an imbalance in hepatic lipid supply, accretion (synthesis and storage), and disposal (export and catabolism) [18]. The prevalence of obesity, hyperlipidemia/dyslipidemia, and type 2 diabetes in NAFLD is estimated at approximately 51 %, 69 %, and 23 %, respectively [1]. Together, these co-morbidities are significant mediators of greater lipid supply to the liver and a remodeled hepatic lipidome. A marked increase in newly synthesized fatty acids via hepatic de novo lipogenesis is another consistent feature of NAFLD that exacerbates lipid deposition [19], [20]. In contrast to the common findings of elevated lipid availability and accretion in NAFLD, fatty acid disposal in hepatic mitochondrial oxidative metabolism pathways exhibit much more functional heterogeneity. This has led to ambiguity as to the role of lipid catabolic pathways in NAFLD and whether they can or should be targeted for therapeutic purposes. Herein, we describe the current state of knowledge regarding the characteristic changes in mitochondrial oxidative metabolism over the natural progression of the disease as well as discuss physiological (hepatic and extra-hepatic) and experimental factors contributing to variations in pathway function. Given that the interplay between lipid homeostasis and inflammation has been considered a key factor in NASH pathophysiology since its initial description in 1980 [21], additional detail is given to well-recognized and emerging mechanisms through which alterations in mitochondrial oxidative metabolism not only impact lipid breakdown but also govern the inflammatory response underlying disease development and progression.
Section snippets
Overview of hepatic lipotoxicity and inflammation
A chronic excess of liver lipids and the resulting lipotoxicity drives the pathophysiology of NAFLD [22]. The accumulation of ‘toxic’ lipids or associated metabolic products instigate and exacerbate the inflammatory and fibrotic features of the disease through the promotion of organelle dysfunction and/or molecular signaling mechanisms [22]. The list of proinflammatory metabolites arising from lipid metabolism is continually increasing, however, the most frequently investigated metabolites
Overview of mitochondrial oxidative metabolism in NAFLD pathogenesis
Fatty acids can be catabolized in microsomes, peroxisomes, and mitochondria [18], [32]. Mitochondrial oxidative metabolism is the primary catabolic process for fatty acids and refers to a cluster of pathways including β-oxidation, citric acid cycle (CAC) flux, oxidative phosphorylation, and, in the liver, ketogenesis [18], [32]. Nutrient flux through each of the mitochondrial oxidative metabolism pathways has been reported to increase, decrease, or remain unchanged in NAFLD (Fig. 1). An
Conclusions and future perspectives
NAFLD is a multifactorial disease characterized by a chronic imbalance between hepatic lipid supply, accretion, and disposal. This impaired lipid homeostasis precipitates the accumulation of toxic lipids and related metabolites that promote inflammatory and fibrotic responses mediating the progressive pathophysiology of the disease. The dysregulation of lipid catabolism in mitochondrial oxidative metabolism pathways is a critical component of inadequate lipid disposal and, consequently,
CRediT authorship contribution statement
Curtis C. Hughey: Conceptualization, Writing – original draft, Writing – review & editing, Visualization. Patrycja Puchalska: Writing – review & editing, Visualization. Peter A. Crawford: Conceptualization, Writing – review & editing.
Declaration of competing interest
PAC has served as a consultant for Pfizer Inc., Abbott Laboratories, and Janssen Research & Development.
Acknowledgments
This work was supported by NIH grants DK091538 (PAC) and AG069781 (PAC), and an American Cancer Society Institutional Research Grant IRG-21-049-61-IRG131 (CCH). Figures were created with BioRender.com.
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