Focus |

Focus on non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. The pathological spectrum of NAFLD ranges from simple steatosis to the necro-inflammatory and fibro-progressive form, non-alcoholic steatohepatitis (NASH), which may then progress to cirrhosis, liver failure and hepatocellular carcinoma. This web focus features papers from Laboratory Investigation and Modern Pathology that present new models and techniques, diagnostic advances, mechanistic insights and potential innovative therapies for NAFLD and NASH.Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. The pathological spectrum of NAFLD ranges from simple steatosis to the necro-inflammatory and fibro-progressive form, non-alcoholic steatohepatitis (NASH), which may then progress to cirrhosis, liver failure and hepatocellular carcinoma. This web focus features papers from Laboratory Investigation and Modern Pathology that present new models and techniques, diagnostic advances, mechanistic insights and potential innovative therapies for NAFLD and NASH.

Photo credit: Ming-Hong Tai

Content

Providing a high fat/calorie diet plus high fructose/glucose in drinking water is shown to be an optimal approach to induce nonalcoholic steatohepatitis in mice. The animal model shows remarkable necroptosis, steatosis, fibrosis and insulin resistance as well as a disordered profile of lipid metabolism and adipokines. This model should prove useful for pathophysiologic investigation and pharmacologic development.

Article | | Laboratory Investigation

In this study, systemic hemodynamics and both aortic and intrahepatic vascular reactivity in a rat model of severe steatosis were investigated. Portal hypertension and signs of a hyperdynamic circulation were demonstrated. NO-independent, COX-2 mediated extrahepatic arterial hyporeactivity, as well as NO-independent alpha-1-adrenergic and endotheline-1 mediated intrahepatic vascular hyperreactivity are demonstrated, likely contributing to the observed portal hypertension in steatosis.

Article | | Laboratory Investigation

Iso-alpha-acids (IAAs) are hops-derived compounds. In this study, the authors show that IAAs inhibit development of non-alcoholic fatty liver disease. They found that IAAs reduced expression of PPAR-γ and key enzymes of lipid synthesis as well as increased expression of PPAR-α, indicative of increased lipid metabolism. IAAs also reduced oxidative stress and JNK-activation, inhibited hepatic stellate cell activation and reduced proliferation and pro-fibrogenic gene expression.

Article | | Laboratory Investigation

Defective thermogenic response to calorie overload contributes to obesity and, in foz/foz mice, to nonalcoholic steatohepatitis (NASH). Activation of brown adipose tissue function by b3AR-agonists together with moderate calorie restriction improves the obese phenotype and resolves NASH pathology. This identifies the brown adipose tissue as a target for adjuvant therapy for NASH.

Article | | Laboratory Investigation

In this paper, the authors determined mechanisms by which aspirin prevents obesity and non-alcoholic fatty liver disease in high-risk mice due to maternal over-nutrition. They provide cellular and molecular evidence that aspirin prevents excessive weight gain, glucose intolerance and hepatic lipid accumulation in female, but not male mice via insulin/Akt and Wnt signaling.

Article | | Laboratory Investigation

The present study reveals that lipotoxicity causes defective mitophagy and excessive mitochondrial reactive oxygen species accumulation. In turn, both events trigger NLRP3 inflammasome activation in fatty acid-overloaded primary hepatocytes. The novel insight advances the understanding of how fatty acids elicit lipotoxicity through oxidant stress and autophagy in mitochondria during progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis.

Article | | Laboratory Investigation

Relaxin-2 reduces liver steatosis in mice with high-fat diet (HFD)-induced non-alcoholic fatty liver disease with simple steatosis or methionine-choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis by activating the eNOS/NO pathway. Additionally, relaxin-2 improves insulin resistance and obesity in HFD mice. In MCD mice, relaxin-2 further attenuates hepatic inflammation and fibrosis with reduction in levels of hepatocyte apoptosis and hepatic stellate cell activation.

Article | | Laboratory Investigation

Pirfenidone prevents lipotoxicity-induced insulin resistance and steatohepatitis by regulating immune cell accumulation and macrophage polarization in the livers of mice. Additionally, pirfenidone suppresses hepatic fibrosis by inhibiting activation of stellate cells and TGF-β1 expression; and reverses insulin resistance, hepatic inflammation, and fibrosis in mice with pre-existing nonalcoholic steatohepatitis.

Article | | Laboratory Investigation

The prolyl hydroxylase domain (PHD) inhibitor JTZ-951 is known to stabilize hypoxia-inducible factors. Mice fed a high-fat diet that were treated with JTZ-951 showed decreased inflammation and fibrosis in white adipose tissue, and exhibited reductions in obesity, hepatic steatosis and albuminuria. These results suggest that PHD inhibition may be a new therapeutic target for obesity-related diseases.

Article | | Laboratory Investigation

The authors identified BMP-2 downregulation in human and experimental fibrotic livers, and found that adenovirus-mediated BMP-2 gene delivery ameliorates liver fibrosis and biliary injury in mice. Mechanistically, BMP-2 suppresses proliferation and migration of hepatic stellate cells by antagonizing TGF-β signaling and epithelial-to-mesenchymal transition. BMP-2 may therefore constitute a therapeutic target for liver fibrosis treatment.

Article | | Laboratory Investigation

S3I-201, a chemical inhibitor of the transcription factor STAT3, suppresses liver fibrogenesis and angiogenesis through multiple mechanisms both in vitro and in vivo. Moreover, S3I-201 and sorafenib, an FDA-approved multikinase inhibitor, function synergistically in suppressing fibrogenesis and angiogenesis of human hepatic stellate cells, indicating high potential for liver fibrosis treatment.

Article | | Laboratory Investigation

The cytoskeletal GTPase SEPT6 is elevated during hepatic stellate cell (HSC) activation and in liver fibrosis. SEPT6 promotes HSC activation, proliferation, cell cycle progression, survival and migration through the TGF-β1/Smad, MAPK and PI3K/AKT signaling pathways. Adenovirus-mediated SEPT6 inhibition attenuates thioacetamide-induced liver fibrosis.

Article | | Laboratory Investigation