Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression

Abstract

Liver sinusoidal endothelial cells (LSECs) are involved in the transport of nutrients, lipids, and lipoproteins, and LSEC injury occurs in various liver diseases including nonalcoholic fatty liver disease (NAFLD). However, the association between LSEC injury and NAFLD progression remains elusive. Accordingly, in this study, we aimed to elucidate the precise role of LSEC in the pathophysiology of NAFLD using two different mouse models, namely the choline-deficient, L-amino acid-defined and high-fat diet models. Administration of these diets resulted in liver metabolic dysregulation mimicking human NAFLD, such as steatosis, ballooning, lobular inflammation, and fibrosis, as well as central obesity, insulin resistance, and hyperlipidemia. LSEC injury appeared during the simple steatosis phase, and preceded the appearance of activated Kupffer cells and hepatic stellate cells (HSCs). These results indicate that LSEC injury may have a 'gatekeeper' role in the progression from simple steatosis to the early nonalcoholic steatohepatitis (NASH) stage, and LSEC injury may be necessary for the activation of Kupffer cells and HSCs, which in turn results in the development and perpetuation of chronic liver injuries. Taken together, our data provide new insights into the role of LSEC injury in NAFLD/NASH pathogenesis.

Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease

“…These morphological changes impair hepatic perfusion and hypoxia, leading to increased activation of hypoxia-inducible factors (HIFs) implicated in the transcriptional regulation of genes involved in angiogenesis, metabolic adaptation, cell survival and proliferation [51]. Several groups described sinusoidal capillarization as an early manifestation of endothelial dysfunction in experimental NAFLD [41,52]. These changes were observed as early as within 1 week after the initiation of choline-deficient, l-amino acid-defined diet, and capillarization has been considered a "gatekeeper" in the progression to steatohepatitis, occurring before the concerted activation of Kupffer cells and HSCs [52].…”

“…Several groups described sinusoidal capillarization as an early manifestation of endothelial dysfunction in experimental NAFLD [41,52]. These changes were observed as early as within 1 week after the initiation of choline-deficient, l-amino acid-defined diet, and capillarization has been considered a "gatekeeper" in the progression to steatohepatitis, occurring before the concerted activation of Kupffer cells and HSCs [52].…”

Adverse effects of antiretroviral therapy on liver hepatocytes and endothelium in HIV patients: An ultrastructural perspective

“…Protease inhibitors (PIs) may cause liver sinusoidal endothelial cells (LSEC), responsible for the transport of nutrients, lipids, and lipoproteins 9,11 , to malfunction by reducing nitric oxide production, and/or under-expression of endothelial nitric oxide synthase 12 . Injuries to the hepatic sinusoids are initial step for liver cirrhosis and other liver diseases 13 .…”

“…Injuries to the hepatic sinusoids are initial step for liver cirrhosis and other liver diseases 13 . LSEC injury appears during the simple steatosis phase and shortly followed by the activation of Kupffer cells and hepatic stellate cells, and which may all lead to the development of chronic liver diseases such as NAFLD or NASH 11 .…”

Arterial hypertension, obesity and non-alcoholic fatty liver disease: is there any connection?

“…The obtained results indicated that the impression of sinusoidal endothelial cells was the "warning signal" of progression of simple steatosis to non-alcoholic steatohepatitis and was a prerequisite for the activation of Kupffer cells and stellate cells of the liver. This determined the development and formation of chronic liver injury [102].…”