Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions

Myint et al. Journal of Translational Medicine https://doi.org/10.1186/s12967-023-04627-0 (2023) 21:757 Journal of Translational Medicine Open Access REVIEW Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions Melissa Myint1, Francesca Oppedisano2, Valeria De Giorgi3, Byeong‑Moo Kim1, Francesco M. Marincola1, Harvey J. Alter3 and Salvatore Nesci4*    Abstract Liver steatosis, inflammation, and variable degrees of fibrosis are the pathological manifestations of nonalcoholic stea‑ tohepatitis (NASH), an aggressive presentation of the most prevalent chronic liver disease in the Western world known as nonalcoholic fatty liver (NAFL). Mitochondrial hepatocyte dysfunction is a primary event that triggers inflammation, affecting Kupffer and hepatic stellate cell behaviour. Here, we consider the role of impaired mitochondrial function caused by lipotoxicity during oxidative stress in hepatocytes. Dysfunction in oxidative phosphorylation and mito‑ chondrial ROS production cause the release of damage-associated molecular patterns from dying hepatocytes, lead‑ ing to activation of innate immunity and trans-differentiation of hepatic stellate cells, thereby driving fibrosis in NASH. Keywords NASH, Mitochondrial dysfunction, Ox-mtDNA, Inflammatory process, Hepatic stellate cells Introduction Non-alcoholic fatty liver (NAFL) is the hepatic manifestation of metabolic syndrome, a collection of conditions that increase risk of coronary heart disease, diabetes, and stroke, amongst other serious health conditions. NALF in particular spans a spectrum of diseases from benign steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma [1]. The pathological characteristic of NAFL is hepatic steatosis, which is defined as an accumulation of fat, in the form of triglycerides, in more than 5% of hepatocytes mostly around the portal vein [2]. The accumulation of fat, caused by disruptions in fatty acid (FA) transport and metabolism, *Correspondence: Salvatore Nesci 1 Sonata Therapeutics, Watertown, MA, USA 2 Department of Health Sciences, Institute of Research for Food Safety and Health, University “Magna Græcia” of Catanzaro, Catanzaro, Italy 3 Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, USA 4 Department of Veterinary Medical Sciences, University of Bologna, Ozzano Emilia, Italy presents phenotypically as lipid droplet (LD) accumulation within hepatocytes. It is the cumulative result of de novo lipogenesis, adipose tissue dysfunction, and obesity-mediated insulin resistance associate to inflammation [3]. All of which impact FA oxidation, mitochondrial metabolism, and lipoprotein trafficking underlying metabolic-associated fatty liver disease (MAFLD) [4–8]. Overexpression of IGF2 in the liver can result in increased LD formation and free cholesterol accumulation, and may thus play a role in the start of steatosis [9]. According to a “classical theory”, NAFL develops through a first “hit” that triggers lipid accumulation and inflammation associated with insulin resistance and progresses through a second “hit” characterized by increased oxidative stress and lipid peroxidation, determining the progression from NAFL to NASH [4, 10]. Additional research refined the two-hit hypothesis into a multiplehit hypothesis, which qualified that the accumulation of triglycerides actually sensitizes the liver to a multitude of secondary insults that include direct lipotoxicity and oxidative stress driven by free radicals from β- and ω-oxidation of free fatty acids (FFAs) [11]. The multiplehit hypothesis also acknowledges contributions from © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Myint et al. Journal of Translational Medicine (2023) 21:757 increased intestinal permeability and alterations in the gut microbiota that result in endotoxin-driven inflammation through activation of Toll-like receptor-4 (TLR4) in Kupffer cells and hepatocytes [11]. Insulin resistance, changes in adipokine secretion, in addition to activation and senescence of hepatic stellate cells (HSCs) all ensue. The cumulative effect is inflammation of the liver and cellular damage, ultimately triggering fibrogenesis [11, 12]. Recent studies have shown a strong association between NAFL and the development of hepatocellular carcinoma even at the non-cirrhotic stage of disease (Fig. 1). The implication is that fatty liver and the associated inflammatory mediators may contribute trigger a pro-tumorigenic condition. Indeed, pro-inflammatory cytokines, such as TNFα or IL-6, contribute to the establishment of chronic inflammation in the adipose liver, enabling the progression to NASH and subsequently carcinoma. This is particularly evident in severely obese patients where levels of intra-hepatic IL-6 are notably high and are reduced with beneficial effects in subjects undergoing bariatric surgery [5, 13]. Moreover, inflammation can play a dominant role in deregulated signaling of the insulin/insulin-like growth factor system (IGFs) in obesity, diabetes, and cancer. In these inflammatory pathological conditions, the multiligand receptor for advanced glycation end-products (RAGEs) is driven by aberrant cross-communication with the impairment of insulin/IGFs in modulating the gene transcription and protein translation in cancer [14]. In addition, in NASH, the oxidative stress of biomolecules in the second hit event generates advanced glycation end products (AGEs), i.e. oxidated sugar reacting with lipids or proteins. AGEs promote the occurrence of NASH by RAGEs interaction through a cascade of downstream signaling triggering oxidative stress, hepatocyte ballooning, and HSCs activation. The effects of AGEs in aggravating NAFL are due to RAGE interaction [15, 16]. Patients with NAFL also suffer high prevalence of other malignancies and cardiovascular Page 2 of 16 diseases suggesting that NAFL alone or in combinatio (...truncated)