Can you write reference papers ( highly cited, high impact journals from last 5 years) supporting the points mentioned in the review article points written here in the text LSECs' Contribution to the Progression of Chronic Liver Diseases (NAFLD, ALD, and Viral Hepatitis)
Liver Sinusoidal Endothelial Cells (LSECs) are pivotal players in the progression of chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and viral hepatitis. In these diseases, LSECs undergo functional and structural changes that compromise their ability to maintain liver homeostasis, leading to inflammation, fibrosis, and eventually cirrhosis.
In NAFLD, a disease characterized by the accumulation of fat in the liver, LSECs contribute to disease progression by becoming dysfunctional as fat accumulation increases. As NAFLD progresses to non-alcoholic steatohepatitis (NASH), LSECs experience capillarization, where they lose their fenestrations and take on characteristics like vascular endothelial cells. This loss of fenestration impairs the ability of LSECs to filter blood properly, leading to reduced clearance of lipids and toxins. Dysfunctional LSECs also produce inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which amplify local inflammation and exacerbate liver injury. These inflammatory signals further promote the activation of hepatic stellate cells (HSCs), leading to increased collagen deposition and fibrosis.
In ALD, chronic exposure to alcohol induces oxidative stress and damages LSECs. Alcohol metabolism generates reactive oxygen species (ROS), which lead to endothelial dysfunction. LSECs in ALD become capillarized and lose their ability to regulate immune tolerance, resulting in excessive immune activation. This immune dysregulation promotes inflammation, hepatocyte death, and fibrosis. Additionally, LSECs in ALD show an increase in the expression of vascular endothelial growth factor (VEGF), a response to hypoxic conditions created by alcohol-induced liver damage. This shift exacerbates angiogenesis and fibrosis, further contributing to the progression of liver disease.
In viral hepatitis (such as hepatitis B and C), LSECs play a crucial role in modulating immune responses. LSECs interact with viral antigens and present them to immune cells, but in the context of chronic infection, this immune interaction becomes dysregulated. Chronic hepatitis leads to sustained inflammation, and LSECs lose their immune-regulatory capacity. In these conditions, LSECs contribute to fibrosis by increasing the expression of pro-fibrotic factors like TGF-β, which activates HSCs. The continuous inflammatory environment created by viral infection drives LSECs to promote both inflammation and fibrogenesis, which accelerates the progression of liver disease to cirrhosis.

Interplay Between LSECs and Other Liver Cells During Liver Disease Progression
The progression of liver disease, from early inflammation to advanced fibrosis and cirrhosis, involves a dynamic interplay between LSECs and other liver cells, including hepatocytes, hepatic stellate cells (HSCs), and immune cells like Kupffer cells. This cellular crosstalk is critical in determining the outcome of liver injury and the rate at which chronic liver diseases progress.
In the early stages of liver disease, such as in NAFLD or viral hepatitis, LSECs play a protective role by maintaining immune tolerance and preventing excessive immune activation. LSECs filter antigens from the bloodstream and communicate with Kupffer cells, the liver’s resident macrophages, to modulate immune responses. However, as liver injury persists, LSECs lose their protective role. Inflammatory signals from damaged hepatocytes and infiltrating immune cells, such as macrophages and neutrophils, trigger LSECs to release pro-inflammatory and pro-fibrotic factors.
As inflammation becomes chronic, LSECs begin to interact with hepatic stellate cells (HSCs) in a more pathological manner. Normally, LSECs release anti-fibrotic signals such as nitric oxide (NO), which keeps HSCs in a quiescent state. However, during liver injury, LSECs reduce NO production and increase the release of TGF-β and PDGF. These signals activate HSCs, causing them to differentiate into myofibroblasts, which produce collagen and other extracellular matrix proteins that lead to fibrosis. This activation of HSCs is a hallmark of the fibrotic response in chronic liver diseases.
In advanced fibrosis and cirrhosis, the liver architecture becomes severely disrupted. LSECs undergo capillarization, losing their fenestrations and their ability to regulate blood flow and filtration. The capillarized LSECs promote further fibrosis by supporting angiogenesis, which is mediated by VEGF. This abnormal blood vessel formation creates a hypoxic environment that perpetuates liver scarring and dysfunction. At this stage, the interplay between LSECs, HSCs, and immune cells becomes a vicious cycle, with continuous collagen deposition, inflammation, and liver remodeling. Cirrhotic livers also show increased interaction between LSECs and macrophages recruited from the bloodstream, which produce additional pro-inflammatory and pro-fibrotic signals, accelerating liver failure.
LSECs are central to both the initiation and progression of liver diseases. From maintaining immune homeostasis in the early stages to contributing to fibrosis and cirrhosis in later stages, LSECs play a dual role in both protecting and damaging the liver, depending on the context of disease and progression. Understanding the mechanisms behind LSEC dysfunction and their interactions with other liver cells offers potential therapeutic targets to halt or reverse liver disease progression.