LECT2 Functions as a Hepatokine That Links Obesity to Skeletal Muscle Insulin Resistance

Abstract

Recent articles have reported an association between fatty liver disease and systemic insulin resistance in humans, but the causal relationship remains unclear. The liver may contribute to muscle insulin resistance by releasing secretory proteins called hepatokines. Here we demonstrate that leukocyte cell–derived chemotaxin 2 (LECT2), an energy-sensing hepatokine, is a link between obesity and skeletal muscle insulin resistance. Circulating LECT2 positively correlated with the severity of both obesity and insulin resistance in humans. LECT2 expression was negatively regulated by starvation-sensing kinase adenosine monophosphate-activated protein kinase in H4IIEC hepatocytes. Genetic deletion of LECT2 in mice increased insulin sensitivity in the skeletal muscle. Treatment with recombinant LECT2 protein impaired insulin signaling via phosphorylation of Jun NH2-terminal kinase in C2C12 myocytes. These results demonstrate the involvement of LECT2 in glucose metabolism and suggest that LECT2 may be a therapeutic target for obesity-associated insulin resistance.

Leukocyte Cell–Derived Chemotaxin 2–Associated Amyloidosis

“…Plasma LECT2 concentration in normal individuals is 19.763.4 ng/ml (37). Its serum level is increased in liver diseases, such as acute liver injury (38), hepatocellular carcinoma (39), fatty liver (40), obesity (40), and insulin resistance (36). In contrast, a recent study showed that plasma LECT2 concentrations in patients with sepsis were remarkably low and negatively correlated with the disease severity (37).…”

“…LECT2 protein was initially purified from a culture fluid of phytohemagglutinin-activated human T cell leukemia SKW-3 cells as a potential chemotactic factor for human neutrophils (24). Subsequent studies indicated that it is a multifactorial cytokine involved in chemotaxis, cell proliferation, immunomodulation, damage/repair process, tumor suppression, and glucose metabolism (33,36,(41)(42)(43)(44).…”

Leukocyte Cell-Derived Chemotaxin 2 Retards Non-Small Cell Lung Cancer Progression Through Antagonizing MET and EGFR Activities

“…In addition to cancer, the circulating level of LECT2 was reported to be correlated with several pathologic conditions. For example, circulating LECT2 was positively correlated with the severity of both obesity and insulin resistance (IR) and was negatively correlated with the severity of sepsis in humans [20,31]. However, the correlation between circulating LECT2 and NSCLC prognoses should be further investigated in future work.…”

Crystal Structure of Human Leukocyte Cell-derived Chemotaxin 2 (LECT2) Reveals a Mechanistic Basis of Functional Evolution in a Mammalian Protein with an M23 Metalloendopeptidase Fold

“…In addition, LECT2 expression inhibited the migration and invasion of human HCC cells in vitro and was negatively correlated with vascular invasion and tumor recurrence in HCC patients (11). In contrast, serum LECT2 levels were positively correlated with the severity of obesity and fatty liver in humans, and overproduction of LECT2 caused the development of obesity-associated insulin resistance (13,14). These findings suggest that LECT2 may be a candidate prognostic marker and a potential therapeutic target for these diseases.…”

“…LECT2 is predominantly expressed in the liver and is a direct target gene of Wnt/␤-catenin signaling (2)(3)(4)(5)(6). Accumulating evidence shows that mammalian LECT2 is a multifunctional protein that is closely associated with several diseases of worldwide concern, including hepatitis (7), rheumatoid arthritis (8 -10), hepatocellular carcinoma (HCC) (11,12), obesity (13,14), and renal and hepatic amyloidosis (15)(16)(17). It has been reported that concanavalin A-induced hepatitis and collagen antibody-induced arthritis were suppressed by LECT2 (7,8).…”