Pcsk9 knockout exacerbates diet-induced non-alcoholic steatohepatitis, fibrosis and liver injury in mice

Abstract

Background & Aims: The fatty acid translocase, also known as CD36, is a well-established scavenger receptor for fatty acid (FA) uptake and is abundantly expressed in many metabolically active tissues. In the liver, CD36 is known to contribute to the progression of non-alcoholic fatty liver disease and to the more severe non-alcoholic steatohepatitis, by promoting triglyceride accumulation and subsequent lipid-induced endoplasmic reticulum (ER) stress. Given the recent discovery that the hepatocyte-secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) blocks CD36 expression, we sought to investigate the role of PCSK9 in liver fat accumulation and injury in response to saturated FAs and in a mouse model of diet-induced hepatic steatosis. Methods: In this study, we investigated the role of PCSK9 on the uptake and accumulation of FAs, as well as FA-induced toxicity, in a variety of cultured hepatocytes. Diet-induced hepatic steatosis and liver injury were also assessed in Pcsk9-/mice. Results: Our results indicate that PCSK9 deficiency in cultured hepatocytes increased the uptake and accumulation of saturated and unsaturated FAs. In the presence of saturated FAs, PCSK9 also protected cultured hepatocytes from ER stress and cytotoxicity. In line with these findings, a metabolic challenge using a high-fat diet caused severe hepatic steatosis, ER stress inflammation and fibrosis in the livers of Pcsk9-/mice compared to controls. Given that inhibition of CD36 ablated the observed accumulation of lipid in vitro and in vivo, our findings also highlight CD36 as a strong contributor to steatosis and liver injury in the context of PCSK9 deficiency. Conclusions: Collectively, our findings demonstrate that PCSK9 regulates hepatic triglyceride content in a manner dependent on CD36. In the presence of excess dietary fats, PCSK9 can also protect against hepatic steatosis and liver injury.

The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury

“…These experimental findings and clinical observations described in this study indicate that the uncleaved proPCSK9 is an important player in ER stress response. In further support of this conclusion, we have recently demonstrated that Pcsk9 -/mice exhibit increased ER stress, inflammation, insulin resistance and liver injury in response to an ER stress-inducing HFD, compared to Pcsk9 +/+ mice (50). Although individuals harboring mutations in PCSK9 that reduce its abundance in the ER or those treated with PCSK9 gene silencing therapies appear healthy, our data suggest that intracellular PCSK9 may play an important role in maintaining the functionality of the UPR.…”

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

“…Recent preclinical studies suggest that PCSK9 and LRP1 could modulate NAFLD pathogenesis. PSCK9 deficiency exacerbated the development of hepatic steatosis in HFD-fed mice [ 112 ]. Moreover, hepatic steatosis decreased cell surface LDLR expression and increased plasma ApoB and total cholesterol in a PCSK9-dependent manner [ 110 ].…”

PCSK9 rs11591147 R46L loss‐of‐function variant protects against liver damage in individuals with NAFLD

“…The reason for not detecting a significant effect in mice fed a chow diet in this study probably relates to the low number of animals used in the chow arm of the experiment related to the main focus on NAFLD. A recent study on C57BL/6J Pcsk9 ‐/‐ mice showed that a high‐fat diet caused severe hepatic steatosis, ER stress inflammation and fibrosis in the livers of Pcsk9 ‐/‐ mice compared to controls 34 . These discrepancies might be related to a different activity of mouse versus human PCSK9, which may be involved in inducing steatosis at intracellular level, and to the diet.…”