NOX5 (NADPH oxidase 5) is a homolog of the gp91 phox subunit of the phagocyte NOX, which generates reactive oxygen species. NOX5 is involved in sperm motility and vascular contraction and has been implicated in diabetic nephropathy, atherosclerosis, and stroke. The function of NOX5 in the cardiac hypertrophy is unknown. Because NOX5 is a Ca 2+ -sensitive, procontractile NOX isoform, we questioned whether it plays a role in cardiac hypertrophy. Studies were performed in (1) cardiac tissue from patients undergoing heart transplant for cardiomyopathy and heart failure, (2) NOX5-expressing rat cardiomyocytes, and (3) mice expressing human NOX5 in a cardiomyocyte-specific manner. Cardiac hypertrophy was induced in mice by transverse aorta coarctation and Ang II (angiotensin II) infusion. NOX5 expression was increased in human failing hearts. Rat cardiomyocytes infected with adenoviral vector encoding human NOX5 cDNA exhibited elevated reactive oxygen species levels with significant enlargement and associated increased expression of ANP (atrial natriuretic peptides) and β-MHC (β-myosin heavy chain) and prohypertrophic genes ( Nppa , Nppb , and Myh7 ) under Ang II stimulation. These effects were reduced by N-acetylcysteine and diltiazem. Pressure overload and Ang II infusion induced left ventricular hypertrophy, interstitial fibrosis, and contractile dysfunction, responses that were exaggerated in cardiac-specific NOX5 trangenic mice. These phenomena were associated with increased reactive oxygen species levels and activation of redox-sensitive MAPK (mitogen-activated protein kinase). N-acetylcysteine treatment reduced cardiac oxidative stress and attenuated cardiac hypertrophy in NOX5 trangenic. Our study defines Ca 2+ -regulated NOX5 as an important NOX isoform involved in oxidative stress- and MAPK-mediated cardiac hypertrophy and contractile dysfunction.
BaCKgRoUND aND aIMS: NAFLD is the most prevalent chronic liver disease without any Food and Drug Administration-approved pharmacological intervention in clinic. Fatty acid synthase (FASN) is one of the most attractive targets for NAFLD treatment because of its robust rate-limiting capacity to control hepatic de novo lipogenesis. However, the regulatory mechanisms of FASN in NAFLD and potential therapeutic strategies targeting FASN remain largely unknown. MetHoDS aND ReSUltS:Through a systematic interactomics analysis of FASN-complex proteins, we screened and identified sorting nexin 8 (SNX8) as a binding partner of FASN. SNX8 directly bound to FASN and promoted FASN ubiquitination and subsequent proteasomal degradation. We further demonstrated that SNX8 mediated FASN protein degradation by recruiting the E3 ligase tripartite motif containing 28 (TRIM28) and enhancing the TRIM28-FASN interaction. Notably, Snx8 interference in hepatocytes significantly deteriorated lipid accumulation in vitro, whereas SNX8 overexpression markedly blocked hepatocyte lipid deposition. Furthermore, the aggravating effect of Snx8 deletion on NAFLD was validated in vivo as hepatic steatosis and lipogenic pathways in the liver were significantly exacerbated in Snx8-knockout mice compared to wild-type controls. Consistently, hepatocytespecific overexpression of Snx8 in vivo markedly suppressed high-fat, high-cholesterol diet (HFHC)-induced hepatic steatosis. Notably, the protective effect of SNX8 against NAFLD was largely dependent on FASN suppression.CoNClUSIoNS: These data indicate that SNX8 is a key suppressor of NAFLD that promotes FASN proteasomal degradation. Targeting the SNX8-FASN axis is a promising strategy for NAFLD prevention and treatment. (Hepatology 2021;74:2508-2525. N AFLD has become the most prevalent chronic liver disease and affects >25% of the population worldwide. (1,2) Hepatic steatosis is the major characteristic of NAFLD and promotes the progression of fatty liver to a more advanced
Background and Aims NAFLD represents an increasing health problem in association with obesity and diabetes with no effective pharmacotherapies. Growing evidence suggests that several FGFs play important roles in diverse aspects of liver pathophysiology. Here, we report a previously unappreciated role of FGF4 in the liver. Approach and Results Expression of hepatic FGF4 is inversely associated with NAFLD pathological grades in both human patients and mouse models. Loss of hepatic Fgf4 aggravates hepatic steatosis and liver damage resulted from an obesogenic high‐fat diet. By contrast, pharmacological administration of recombinant FGF4 mitigates hepatic steatosis, inflammation, liver damage, and fibrogenic markers in mouse livers induced to develop NAFLD and NASH under dietary challenges. Such beneficial effects of FGF4 are mediated predominantly by activating hepatic FGF receptor (FGFR) 4, which activates a downstream Ca2+–Ca2+/calmodulin‐dependent protein kinase kinase beta–dependent AMP‐activated protein kinase (AMPK)‐Caspase 6 signal axis, leading to enhanced fatty acid oxidation, reduced hepatocellular apoptosis, and mitigation of liver damage. Conclusions Our study identifies FGF4 as a stress‐responsive regulator of liver pathophysiology that acts through an FGFR4‐AMPK‐Caspase 6 signal pathway, shedding light on strategies for treating NAFLD and associated liver pathologies.
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