Hepatic stellate cells secrete Ccl5 to induce hepatocyte steatosis

Abstract

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of disease severity, starting from pure steatosis, leading to fatty inflammation labeled as non-alcoholic steatohepatitis (NASH), and finally fibrosis leading to cirrhosis. Activated hepatic stellate cells (HSCs) are known to contribute to fibrosis, but less is known about their function during NAFLD’s early stages prior to fibrosis. We developed an ex vivo assay that cocultures primary HSCs from mouse models of liver disease with healthy hepatocytes to study their interaction. Our data indicate that chemokine Ccl5 is one of the HSC-secreted mediators in early NASH in humans and in mice fed with choline-deficient, L-amino acid defined, high fat diet. Furthermore, Ccl5 directly induces steatosis and pro-inflammatory factors in healthy hepatocytes through the receptor Ccr5. Although Ccl5 is already known to be secreted by many liver cell types including HSCs and its pro-fibrotic role well characterized, its pro-steatotic action has not been recognized until now. Similarly, the function of HSCs in fibrogenesis is widely accepted, but their pro-steatotic role has been unclear. Our result suggests that in early NASH, HSCs secrete Ccl5 which contributes to a broad array of mechanisms by which hepatic steatosis and inflammation are achieved.

A blocking monoclonal antibody to CCL24 alleviates liver fibrosis and inflammation in experimental models of liver damage

“…For example, Kim et al recently reported that CCR5 is expressed on hepatocytes and is involved in their ability to accumulate fat and promote steatosis and that CCL5 is secreted by hepatocytes during steatosis. [43][44][45] Our data suggest that there might be a direct effect of CCL24 on hepatocytes, although an indirect effect could not be completely ruled out. This effect, either direct or indirect, is novel and highly interesting and needs to be further elucidated in upcoming research on CCL24.…”

Nonalcoholic Fatty Liver Disease

“…These findings were further confirmed in humans, showing increased circulating CCL20 protein levels in patients with NAFLD-related fibrosis (Chu et al 2018). Further data based on an elegant co-culturing system using primary liver cells pointed toward CCL5 as an important hepatic stellate cell-derived chemokine capable of mediating steatosis and pro-inflammatory responses in initially healthy hepatocytes (Kim et al 2018). Moreover, in vivo induction of CCL5 in response to high-fat diet was also shown to serve as an important regulator of vascular remodeling, revealing a role for CCL5 and its receptor in atherogenesis (Lin et al 2018).…”

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

“…Nonparenchymal hepatic cell types, including hepatic stellate cells (HSCs), contribute to coordinated fibrosis and progression towards NAFLD [67]. High levels of saturated FAs from the diet lead to the activation of HSCs, which, in turn, upregulate the production of proinflammatory cytokines (IL-34 and CCL5) [67,68]. Through lipid droplet breakage, HSCs remain a source of bioactive lipid species that may act extracellularly within the liver, enhance the lipotoxic effect of fat spillover and lead to a more severe spectrum of NAFLD [69].…”