The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease

Abstract

The increased production of reactive oxygen species (ROS) has been postulated to play a key role in the progression of nonalcoholic fatty liver disease (NAFLD). However, the source of ROS and mechanisms underlying the development of NAFLD have yet to be established. We observed a significant up-regulation of a minor isoform of NADPH oxidase, NOX1, in the liver of nonalcoholic steatohepatitis (NASH) patients as well as of mice fed a high-fat and high-cholesterol (HFC) diet for 8 weeks. In mice deficient in Nox1 (Nox1KO), increased levels of serum alanine aminotransferase and hepatic cleaved caspase-3 demonstrated in HFC diet-fed wild-type mice (WT) were significantly attenuated. Concomitantly, increased protein nitrotyrosine adducts, a marker of peroxynitrite-induced injury detected in hepatic sinusoids of WT, were significantly suppressed in Nox1KO. The expression of NOX1 mRNA was much higher in the fractions of enriched liver sinusoidal endothelial cells (LSECs) than in those of hepatocytes. In primary cultured LSECs, palmitic acid (PA) up-regulated the mRNA level of NOX1, but not of NOX2 or NOX4. The production of nitric oxide by LSECs was significantly attenuated by PA-treatment in WT but not in Nox1KO. When the in vitro relaxation of TWNT1, a cell line that originated from hepatic stellate cells, was assessed by the gel contraction assay, the relaxation of stellate cells induced by LSECs was attenuated by PA treatment. In contrast, the relaxation effect of LSECs was preserved in cells isolated from Nox1KO. Taken together, the up-regulation of NOX1 in LSECs may elicit peroxynitrite-mediated cellular injury and impaired hepatic microcirculation through the reduced bioavailability of nitric oxide. ROS derived from NOX1 may therefore constitute a critical component in the progression of NAFLD.

Inflammation in Primary and Metastatic Liver Tumorigenesis–Under the Influence of Alcohol and High-Fat Diets

“…Interruption of blood flow by tumor cell obstruction of the sinusoidal vasculature can lead to transient ischemia which induces tumoricidal inflammation owing to the release of ROS, nitric oxide (NO), TNF-α and interferon-γ (IFN-γ) by LSECs and KCs [153,155,157]. Similarly, HFD in mice also increased the levels of reactive ROS produced from LSECs [158], and increasing NAFLD severity was associated with a pro-inflammatory gene expression signature in LSECs which included increased COX-2, NOX-2 and IL-6 levels [145]. HFD-induced CLD could therefore potentiate elimination of disseminated tumor cells invading the liver sinusoid.…”

Nonalcoholic Fatty Liver Disease

“…Lipotoxic responses also affect LSECs, a type of non-parenchymal cell that is specifically involved in maintaining hepatic vascular tone and quiescence of hepatic stellate cells that are responsible for the fibrotic response. Upon treatment with oxidized lipids (Zhang et al 2014) or palmitic acid (Matsumoto et al 2018), LSCEs directly or indirectly triggered the release of reactive oxygen species (ROS) production (Peters et al 2018), which influences mechanisms related to inflammation and fibrosis (Ni et al 2017).…”

NOX1 Inhibition Attenuates the Development of a Pro-Tumorigenic Environment in Experimental Hepatocellular Carcinoma

“…alcohol abuse, viral hepatitis, obesity, cholestatic liver injury) induces liver injury characterized by a microenvironment abundant of various types of cellular stress, including endoplasmic reticulum stress, cellular DNA damage, necrosis of damaged hepatocytes, and oxidative stress with reactive oxygen species (ROS) production. In the liver, ROS are generated in response to a wide variety of endogenous and exogenous stimuli (2)(3)(4)(5)(6). ROS species play multiple biological roles and are therefore involved in a large number of physiological phenomena, such as host defense, but also posttranslational protein processing, cellular signalling, regulation of gene expression, and cellular differentiation (7)(8)(9).…”