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Endocrinology. 2014 Dec;155(12):4697-705. doi: 10.1210/en.2014-1430. Epub 2014 Oct 3.

Osteocalcin protects against nonalcoholic steatohepatitis in a mouse model of metabolic syndrome.

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Bioenergetics Program (A.A.G.), Houston Methodist Research Institute, Houston, Texas; Department of Surgery (O.M.S., D.F., S.A., A.O.G.), Houston Methodist Hospital, Houston, Texas 77030; Immunobiology Research Center (L.J.M.), Houston Methodist Research Institute, Houston, Texas 77030; Department of Microbiology, Immunology and Biochemistry (S.K.N.), University of Tennessee Health Science Center, Memphis, Tennessee 38163; Houston Methodist Research Institute (J.Z.L., C.J.L., W.A.H.), Methodist Diabetes and Metabolism Institute, Houston, Texas 77030; Department of Pathology (L.G.), Houston Methodist Hospital, Houston, Texas 77030; and Department of Medicine (J.Z.L., W.A.H.), Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210.


Nonalcoholic fatty liver disease, particularly its more aggressive form, nonalcoholic steatohepatitis (NASH), is associated with hepatic insulin resistance. Osteocalcin, a protein secreted by osteoblast cells in bone, has recently emerged as an important metabolic regulator with insulin-sensitizing properties. In humans, osteocalcin levels are inversely associated with liver disease. We thus hypothesized that osteocalcin may attenuate NASH and examined the effects of osteocalcin treatment in middle-aged (12-mo-old) male Ldlr(-/-) mice, which were fed a Western-style high-fat, high-cholesterol diet for 12 weeks to induce metabolic syndrome and NASH. Mice were treated with osteocalcin (4.5 ng/h) or vehicle for the diet duration. Osteocalcin treatment not only protected against Western-style high-fat, high-cholesterol diet-induced insulin resistance but substantially reduced multiple NASH components, including steatosis, ballooning degeneration, and fibrosis, with an overall reduction in nonalcoholic fatty liver disease activity scores. Further, osteocalcin robustly reduced expression of proinflammatory and profibrotic genes (Cd68, Mcp1, Spp1, and Col1a2) in liver and suppressed inflammatory gene expression in white adipose tissue. In conclusion, these results suggest osteocalcin inhibits NASH development by targeting inflammatory and fibrotic processes.

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