Preliminary evidence that adipose tissue contributes to serum proprotein convertase subtilisin/kexin type 9 levels in murine models of metabolic liver injury

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with obesity. Excess cholesterol, the hepatic and circulating levels of which are regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9), exacerbates MASLD. Data on hepatic and circulating PCSK9 protein expression in MASLD are inconsistent, and PCSK9 levels in different adipose tissues have not been well studied. Here, we used two MASLD mouse models that develop hepatic steatosis, one with weight gain and one with weight loss. These models enable distinguishing between the effects of obesity and MASLD. In the high-fat diet model, hepatic PCSK9 protein was normal. PCSK9 protein was increased in the serum and epididymal fat of the mice. In mice fed a methionine-choline-deficient diet, PCSK9 protein was normal in the liver, brown fat, subcutaneous fat, epididymal, and perirenal adipose tissue. Serum PCSK9 levels were reduced, suggesting that the lower fat mass of these mice contributed to the reduction. It is noteworthy that PCSK9 expression was low in adipocytes compared to hepatocytes. In addition, stromal vascular cells residing within adipose tissue contribute to PCSK9 protein levels in adipose tissue. PCSK9 protein was similar in subcutaneous, epididymal, and perirenal adipose tissue and was lowest in brown adipose tissue, indicating a more prominent expression in white adipose tissues. The current study shows that PCSK9 is expressed in both white and brown adipose tissues, and suggests that obesity rather than liver steatosis is associated with higher serum PCSK9 levels.