Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, which begins with isolated steatosis and advances to nonalcoholic steatohepatitis (NASH), steatofibrosis, and cirrhosis. The pathways involved in disease progression are not understood. Loss-of-function mutations in Wnt coreceptor LDL receptor-related protein 6 (LRP6) underlie early-onset atherosclerosis, metabolic risk factors, and NAFLD in humans by unknown mechanisms. We generated mice with the human disease-associated LRP6(R611C) mutation and phenotypically characterized their liver. Homozygote LRP6(R611C) (LRP6(mut/mut)) mice exhibited both steatohepatitis and steatofibrosis. These traits were associated with increased activity of the noncanonical Wnt/Ras homolog family member A, Rho-associated protein kinase 2, and PKC-α/-μ pathways. Accordingly, there was increased TGF-β1 activity, coupled with enhanced expression of smooth muscle α-actin and vimentin that colocalized with albumin in LRP6(mut/mut) mouse liver. LRP6 knockdown reprogramed HepG2 cells to express both these markers, linking impaired Wnt signaling with hepatocyte transdifferentiation. The causal link between altered Wnt signaling and NASH was established by normalization of the disease pathways and rescue of the liver traits by Wnt3a administration to LRP6(mut/mut) mice. Thus, this study identifies diverse disease pathways that underlie a spectrum of NASH-related liver diseases and are linked by a single human genetic variant. LRP6 and noncanonical Wnt pathways are important potential therapeutic targets against NASH.
*Yale Cardiovascular Research Center, Department of Internal Medicine, Yale Liver Center, and Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Geriatric Cardiology and The Cardiology Department, Chinese Peoples' Liberation Army General Hospital & Medical School, Beijing, China; and Department of Food and Nutrition, Kookmin University, Seoul, South Korea.
Shuxia
S
Wang
*Yale Cardiovascular Research Center, Department of Internal Medicine, Yale Liver Center, and Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Geriatric Cardiology and The Cardiology Department, Chinese Peoples' Liberation Army General Hospital & Medical School, Beijing, China; and Department of Food and Nutrition, Kookmin University, Seoul, South Korea.
Kangxing
K
Song
*Yale Cardiovascular Research Center, Department of Internal Medicine, Yale Liver Center, and Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Geriatric Cardiology and The Cardiology Department, Chinese Peoples' Liberation Army General Hospital & Medical School, Beijing, China; and Department of Food and Nutrition, Kookmin University, Seoul, South Korea.
Roshni
R
Srivastava
*Yale Cardiovascular Research Center, Department of Internal Medicine, Yale Liver Center, and Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Geriatric Cardiology and The Cardiology Department, Chinese Peoples' Liberation Army General Hospital & Medical School, Beijing, China; and Department of Food and Nutrition, Kookmin University, Seoul, South Korea.
Chao
C
Dong
*Yale Cardiovascular Research Center, Department of Internal Medicine, Yale Liver Center, and Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Geriatric Cardiology and The Cardiology Department, Chinese Peoples' Liberation Army General Hospital & Medical School, Beijing, China; and Department of Food and Nutrition, Kookmin University, Seoul, South Korea.
Gwang-Woong
GW
Go
*Yale Cardiovascular Research Center, Department of Internal Medicine, Yale Liver Center, and Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Geriatric Cardiology and The Cardiology Department, Chinese Peoples' Liberation Army General Hospital & Medical School, Beijing, China; and Department of Food and Nutrition, Kookmin University, Seoul, South Korea.
Na
N
Li
*Yale Cardiovascular Research Center, Department of Internal Medicine, Yale Liver Center, and Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Geriatric Cardiology and The Cardiology Department, Chinese Peoples' Liberation Army General Hospital & Medical School, Beijing, China; and Department of Food and Nutrition, Kookmin University, Seoul, South Korea.
Yasuko
Y
Iwakiri
*Yale Cardiovascular Research Center, Department of Internal Medicine, Yale Liver Center, and Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Geriatric Cardiology and The Cardiology Department, Chinese Peoples' Liberation Army General Hospital & Medical School, Beijing, China; and Department of Food and Nutrition, Kookmin University, Seoul, South Korea arya.mani@yale.edu.
Arya
A
Mani
D000199:Actins / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation / Q000502:physiology; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060509:Wnt3A Protein / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism
D000199:Actins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D053773:Transforming Growth Factor beta1; D014746:Vimentin; D060509:Wnt3A Protein; C089212:protein kinase D; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha
LRP6; PKC; ROCK; RhoA; hepatic steatosis