bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diabetes Remission Clinical Trial (DiRECT)—Plasma Liver Function Tests Reflect Change in Liver Fat Content in Early Type 2 Diabetes
Authors: ZHYZHNEUSKAYA SVIATLANA V. , AL-MRABEH AHMAD , PETERS CARL , BARNES ALISON C. , HOLLINGSWORTH KIEREN G. , PILKINGTON HELEN , WELSH PAUL , SATTAR NAVEED , LEAN MICHAEL E. , TAYLOR ROY 
Published: June 2018

We have evaluated changes in liver function tests and liver fat following 12-month weight change in the Tyneside participants of the prospective, randomised Diabetes Remission Clinical Trial (DiRECT). Complete data were available on 45 of the Intervention group participants. The group was typical of early type 2 diabetes: 53.7±1.2 years; 56% male; weight 99.6±2.6 kg; BMI 34.6±0.7 kg/m2, diabetes duration 3.3±0.2 years. Fasting liver fat content was measured by 3-point Dixon MRI.
Baseline fasting plasma glucose was 157±7 mg/dl, with liver fat grossly elevated at 16.2±1.5% (mean±SEM; upper level of normal 5.5%). Mean weight loss was 11.5±1.1 kg (0-37kg) and liver fat was normalised at 4.7±0.9% (p&lt;0.0001). With weight losses of &gt;10kg, 5-10kg, &lt;5kg, liver fat decreased to 1.9±0.3%, 5.9±1.4% and 10.2±2.2% respectively. ALT decreased by 51% (32.5±3.0 to 16.0±1.1 U/l; p&lt;0.0001), 37% (31.8±3.8 to 19.9±3.7U/l; p=0.002), and 35% (24.8±4.7 to16.1±1.6 U/l; p=0.058) respectively. Similar reductions were observed in GGT, by 53% (p&lt;0.0001), 35% (p=0.003), 26% (p= 0.05) respectively. Lesser changes were observed in AST, by 29% (p&lt;0.0001), 20% (p=0.29), and 28% (p=0.012) respectively. There were positive correlations between changes in liver fat and ALT (r=0.6, p&lt;0.0001), GGT (r=0.4, p=0.009) and AST (r=0.4, p=0.016). Change in liver fat correlated with weight change (r=0.5, p&lt;0.0001).
Following weight loss in type 2 diabetes, changes in ALT and GGT reflect change in liver fat even within the normal range. Early type 2 diabetes is associated with severe nonalcoholic fatty liver disease, and monitoring change by a simple inexpensive blood test is important in clinical practice.

Disclosure
S.V. Zhyzhneuskaya: None. A. Al-Mrabeh: None. C. Peters: None. A.C. Barnes: None. K.G. Hollingsworth: None. H. Pilkington: None. P. Welsh: Research Support; Self; Boehringer Ingelheim GmbH, Theracos, Inc. N. Sattar: Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, Medscape, Sanofi-Aventis Deutschland GmbH. M.E. Lean: Advisory Panel; Self; Novo Nordisk Inc., Orexigen Therapeutics, Inc.. Research Support; Self; Cambridge Weight Plan. Consultant; Self; Counterweight Ltd. Stock/Shareholder; Self; Eat Balanced. R. Taylor: None.
A Porcine Placental Extract Alleviates Lipotoxicity-Induced NASH by Polarizing M2 Macrophages and Attenuating Stellate Cell Activation in Mice
Authors: CHEN GUANLIANG , XU LIANG , NAGATA NAOTO , NAGASHIMADA MAYUMI , OTA TSUGUHITO 
Published: June 2018

NAFLD is caused by excessive hepatic lipid accumulation and associated with activation of macrophage/Kupffer cells and oxidative stress, resulting in nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Placental extracts have been used to treat various chronic diseases due to their antioxidative effect. However, the effects of the extracts on the development of NASH have yet to be elucidated. Here, we investigated the effect of porcine placental extract (PPE) in a lipotoxicity-induced NASH model. C57BL/6 mice were fed a high-cholesterol, high-fat (CL) diet or a CL diet containing 0.1% PPE (CL+0.1%PPE) or 0.3% PPE (CL+0.3%PPE). Liver histology and fibrogenesis were examined. In addition, intrahepatic immune cell numbers were quantified by flow cytometry. After 15 weeks of administration, PPE alleviated lipid accumulation by reducing hepatic TG, TC and NEFA levels, as well as lipid peroxidation, which was assessed by TBARS. PPE improved glucose intolerance and enhanced the insulin signal, assessed by IRβ and Akt phosphorylation, in the liver, which was associated with the attenuation of MAPK (ERK/p38MAPK) and NF-kB activation. Flow cytometry analysis revealed that PPE reduced CD11c+CD206−(M1) by 44.2%, whereas it increased CD11c-CD206+(M2) by 1.4-fold, resulting in a predominance of M2 over M1 macrophage populations in the liver of NASH mice. In addition, PPE downregulated LPS-induced M1 marker mRNA expression in isolated murine peritoneal macrophages, but augmented IL-4-induced M2 marker mRNA expression in a dose-dependent manner. Furthermore, the PPE reduced the hepatic stellate cell (HSC) activation associated with the attenuated transforming growth factor-β/Smad3 signaling, both in the liver of NASH mice and in HSC line. Thus, PPE may be a potential approach to prevent NASH by limiting lipid peroxidation, promoting M2 macrophage polarization, and attenuating HSC activation.

Disclosure
G. Chen: None. L. Xu: None. N. Nagata: None. M. Nagashimada: None. T. Ota: None.
Hepatic Insulin Signaling Regulates Hepatokines to Coordinate Energy Expenditure and Weight Gain through Irs2 in Sim1 Neurons
Authors: TAO RONGYA , COPPS KYLE D. , STOEHR OLIVER , WHITE ORRIS F. 
Published: June 2018

Insulin resistance is the underlying cause of type 2 diabetes; however, insulin resistance might also be a feed-back mechanism to protect cells and tissues from acute effects of over nutrition. Based upon our results with LDKO (hepatic specific Irs1L/LIrs2L/L CreAlbumin) mice, we found that hepatic insulin resistance elevated systemic oxygen consumption and energy expenditure, which was associated with a dramatic reduction of the RER (respiratory exchange ratio) and resistance to diet-induced obesity. Deletion of hepatic FoxO1 in LDKO-mice restored energy homeostasis and oxygen consumption, and increased the RER into the normal range. Contrary to the progressive peripheral insulin resistance of the LDKO-mice, Irs2 expression and insulin sensitivity increased in the PVH (paraventricular nucleus of hypothalamus). Interestingly, deletion of Irs2 in the PVH (Irs2L/L-mice intercrossed with CreSim1-mice) increased body weight and promoted obesity. To identify the molecular cross-talk between liver and brain, we used a neuronal cell line to screen for the effects of hepatokines that were dysregulated in LDKO-mice—but normalized in LTKO-mice. Among these dysregulated hepatokines, excess circulating NTF3 and GPX3 led to increased Irs2 expression and insulin sensitivity in neurons. Thus, our study suggests that hepatic FoxO1-dependent hepatokines—NTF3 or GPX3—modulate systemic energy expenditure and body weight through Irs2 expression in the PVH.

Disclosure
R. Tao: None. K.D. Copps: None. O. Stoehr: None. M.F. White: Advisory Panel; Self; Housey Pharmaceutical Research Laboratories.
mGPDH Depress Hepatic Lipogenesis by Inhibition of ER Stress
Authors: ZHENG YI , ZHENG HONGTING 
Published: June 2018

Background: NAFLD is the most common liver disorder worldwide. Mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a component of respiratory chain, and reported to involve in hepatic glucose homeostasis, however its function in hepatic lipid metabolism is unclear. We previously observed a low mGPDH expression in fatty liver. Thus, this study is to determine the role of mGPDH in liver lipid metabolism and steatosis.
Methods: mGPDH-/- mice were fed chow or HFD. ob/ob and HFD mice were treated adenovirus-associated virus (AAV) 8-mGPDH. Hepatic and plasma lipid profile were assessed. Livers were analyzed by histology, qRT-PCR and immunoblot. RNA-sequencing was performed using hepatocyte LO2 infected mGPDH under FFA.
Results: In fatty livers of NAFLD patients and mice (ob/ob, HFD and db/db), mGPDH expression is inhibited. Livers of mGPDH-/- mice become sensitivity to HFD and potentiate to steatosis. Mechanistically, RNA-sequencing reveals mGPDH regulates endoplasmic reticulum (ER)-related proteins, and we further confirm its effect on depressing hepatic lipogenesis is mainly through inhibiting ER stress by activation of the IRE1α branch of the UPR. Moreover, rescuing hepatic mGPDH deficient in ob/ob and HFD mice by liver target AAV8 may be a mechanism for ameliorating hepatic steatosis.
Conclusions: mGPDH serves as a novel suppressor for hepatic lipogenesis, and direct targeting of mGPDH may have therapeutic potential for NAFLD.

Disclosure
Y. Zheng: None. H. Zheng: None.
Ethnic Differences in Hepatic Insulin Clearance Seen since Childhood Suggest a Genetic Basis
Authors: PICCININI FRANCESCA , POLIDORI DAVID , GOWER BARBARA , FERNANDEZ JOSE R. , BERGMAN RICHARD N. 
Published: June 2018

African American (AA) adult women (AAw) have 1/3 the hepatic insulin extraction as European American adult women (EAw). Lower hepatic (but not extrahepatic) insulin clearance in AAw contributes to hyperinsulinemia. Our aim was to examine whether hepatic insulin clearance impairment exists in AA since childhood. If so, genetic factors might explain ethnic differences in insulin clearance. The FSIGT was performed on 203 children [55 AAc, 88 EAc, 60 HAc (Hispanic American), ages 7-13 years, mean BMI = 19 kg/m2, basal plasma glucose = 99 mg/dL, insulin = 78 pM, C-peptide = 511 pM]. Data were analyzed with a recent mathematical model providing individual estimates of both hepatic fractional insulin extraction (FEL) and extrahepatic insulin clearance (CLP). Results are presented as mean (SD). Two-way ANOVA and ANCOVA were done: sex and ethnicity were used as groups for both the analysis, while age, Tanner stage and body fat from DXA were the covariates. FEL is lower in AAc (19% (20%)) than EAc (33% (20%)), p = 0.0007). Adjusting for the covariates, ethnicity was still associated with lower FEL in AAc vs. EAc (p = 0.0012); sex had a slight but significant effect (FEL=24% (10%) in boys vs. 29% (10%) in girls, p = 0.04). FEL in HAc (28% (21%)) was not significantly different than either AAc or EAc (p&gt;0.05), with or without covariates correction. No correlation between FEL and age was found in these children. Unlike FEL, CLP was not impacted by ethnicity or sex; similar values were observed among the three groups [27 (12), 21 (12), and 24 (28) mL/kg/min for AAc, HAc, and EAc, respectively; p &gt; 0.05]. As the between-group differences in FEL are seen early in childhood, this suggests genetic factors likely contribute to those, rather than lifestyle, that might have a less evident effect at that age, instead. Playing a more important role than previously realized, the reduced insulin degradation would lead to hyperinsulinemia, insulin resistance, and possibly greater risk for type 2 diabetes in AA, compared to other ethnic groups.

Disclosure
F. Piccinini: None. D. Polidori: Employee; Self; Janssen Research & Development. Stock/Shareholder; Self; Janssen Research & Development. B. Gower: None. J.R. Fernandez: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S.
The Molecular Role of WNT5A and Its Antagonist SFRP5 in Gluconeogenesis and Inflammation in Human Hepatocytes
Authors: CARSTENSEN-KIRBERG MAREN , NIERSMANN CORINNA , ROEHRIG KARIN , RODEN MICHAEL , HERDER CHRISTIAN 
Published: June 2018

The wingless-related MMTV integration site (WNT)5A has pro-inflammatory effects and induces insulin resistance in mice. The secreted frizzled-related protein 5 (SFRP5) blocks the deleterious effects of WNT5A in mice. In humans, the interaction of WNT5A and SFRP5 in the pathogenesis of type 2 diabetes is almost unknown. Therefore, the aim of this study was to characterize the interplay of WNT5A and SFRP5 in glucose metabolism and inflammation in human hepatocytes. We treated the human HepaRG cell line without or with (i) 5 ng/ml WNT5A, (ii) 5000 ng/ml SFRP5 as well as (iii) 5 ng/ml WNT5A and 5000 ng/ml SFRP5 for 24 h. The mRNA levels of key enzymes of the gluconeogenesis were measured using real-time PCR. We analyzed 92 inflammatory proteins in the supernatant using the OLINK inflammation panel. Total and phosphorylated protein content of markers of inflammatory pathways were analysed using Western blotting. WNT5A increased mRNA levels of phosphoenolpyruvate carboxykinase (PCK)2 and glucose-6-phosphatase catalytic subunit (G6PC) by 50% and 196% compared to control (p&lt;0.05). Interestingly, the co-treatment with SFRP5 decreased PCK2 and G6PC mRNA by 36% and 48% compared to control (p&lt;0.05). In addition, WNT5A reduced the secretion of protein levels of 23 pro-inflammatory proteins in the supernatant on average by 56% compared to control (p&lt;0.05). Most of these proteins were chemokines (e.g., CXCL5, CCL2) and cytokines (e.g., IL-6, IL-18). WNT5A also decreased the phosphorylation level of NF-κB by 39% (p&lt;0.01). The co-treatment with SFRP5 led to a secretion profile similar to control.
In conclusion, contrary to mouse models, WNT5A has anti-inflammatory properties in human HepaRG which might be mediated by inactivation of the NF-κB signaling pathway. Nevertheless, WNT5A adversely affects the expression of gluconeogenic enzymes. SFRP5 antagonizes both beneficial and harmful hepatic effects of WNT5A.

Disclosure
M. Carstensen-Kirberg: None. C. Niersmann: None. K. Roehrig: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. C. Herder: Other Relationship; Self; Sanofi, Eli Lilly and Company.
Hypothalamic Orexin Is Essential for Estrogenic Action on Glucose and Energy Metabolism in Diet-Induced Obese Mice
Authors: KON KANTA , TSUNEKI HIROSHI , TAKATA SHINJIRO , MAEDA TAKAHIRO , WADA TSUTOMU , SASAOKA TOSHIYASU 
Published: June 2018

Decreased estrogen is a crucial pathogenic factor for type 2 diabetes in postmenopausal women; however, the precise mechanism remains unknown. Orexin is a major hypothalamic neuropeptides regulating energy/glucose metabolism, and its anti-obese effect is more evident in females. We therefore investigated whether estrogen prevents obesity and glucose intolerance through interaction with the orexin system. Ovariectomized (OVX) mice and female orexin knockout (OXKO) mice were prepared to examine the impact of estrogen and orexin deficiency, respectively. When maintained on 60% high fat diet (HFD) for 16-24 weeks, body weight gain, adipose tissue inflammation, and hepatic triglyceride contents were markedly increased in OXKO, compared to wild type (WT) mice. Ovariectomy did not significantly affect the body weight in WT and OXKO mice after prolonged HFD feeding. Importantly, the levels of proinflammatory markers (e.g., TNFα mRNA) in the white adipose tissues were increased mildly in sham-operated OXKO (Sham-OXKO) mice and remarkably in OVX-OXKO mice. The rank order of the severity was OVX-OXKO&gt;Sham-OXKO&gt;OVX-WT&gt;Sham-WT. Moreover, Sirius-Red staining to evaluate the fatty liver disease (i.e., NAFLD/NASH) demonstrated mild and severe fibrosis in the liver of Sham-OXKO and OVX-OXKO mice, respectively, whereas there was no abnormality in OVX-WT and Sham-WT mice. In glucose tolerance test, 1) metabolic activity was greater in Sham-WT than OVX-WT mice, whereas no difference was observed between Sham-OXKO and OVX-OXKO mice on HFD, 2) intracerebroventricular injection of estrogen improved glucose tolerance in OVX-WT but not OVX-OXKO mice on HFD, suggesting that estrogen prevents glucose intolerance on HFD in an orexin-dependent manner. Taken together, orexin may play a fundamental role in the anti-obese and antidiabetic effects of estrogen. Therefore, orexin appears to be a novel therapeutic target to prevent metabolic disorders in postmenopausal women.

Disclosure
K. Kon: None. H. Tsuneki: None. S. Takata: None. T. Maeda: None. T. Wada: Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. T. Sasaoka: None.
Metabolic Activity of the Liver during Exercise—A Metabolomics Approach
Authors: PLOMGAARD PETER , HU CHUNXIU , HANSEN JAKOB S. , ZHAO XINJIE , HOENE MIRIAM , WANG XIAOLIN , SECHER NIELS , HAERING HANS-ULRICH , LEHMANN RAINER , XU GUOWANG , WEIGERT CORA 
Published: June 2018

The liver plays a pivotal role in substrate metabolism during fasting and exercise. Chances in the hepatic uptake or release of metabolites regulate the hepatic energy supply for other organs. Here we evaluated substrate flow over the hepato-splanchnic bed by assessing arterial-to-venous differences based on UPLC and CE-MS metabolomics analysis at rest and during exercise. Catheterized healthy young male subjects (n = 10) performed 2 h of ergometer cycling followed by 4 h of recovery. In response to exercise there was pronounced hepatic uptake of lactate, pyruvate, various amino acids and dicarboxylic acids, indicating high demand for gluconeogenic substrates and increase in anaplerotic reactions of the citric acid cycle. Medium chain fatty acids e.g., caproic acid showed a clear hepatic uptake during exercise, underlining their potential role as regulators of gluconeogenesis and mitochondrial substrate oxidation. While most long chain fatty acids showed increased hepatic uptake, saturated fatty acids with carbon chain &gt; 18 were released. In contrast to other amino acids, branched chain amino acids were not taken up or released from the liver at any time point. Notably, the hepato-splanchnic bed showed pronounced uptake of oxygen and release of CO2 during exercise indicating up-regulation of energy consuming metabolic processes.
In conclusion, the data provide novel insight in the regulation of hepatic metabolism at rest and during exercise.

Disclosure
P. Plomgaard: None. C. Hu: None. J.S. Hansen: Employee; Self; Novo Nordisk A/S. X. Zhao: None. M. Hoene: None. X. Wang: None. N. Secher: None. H. Haering: None. R. Lehmann: None. G. Xu: None. C. Weigert: None.
Characterization of the G2L1 Interactome Leads to the Discovery That CLIP2, G2L1, and EB1 Undergo Insulin-Stimulated Phosphorylation
Authors: BARKER NATALIE K. , KRANTZ JAMES L. , PARKER SARA , MOUNEIMNE GHASSAN , LANGLAIS PAUL R. 
Published: June 2018

G2L1 is a member of the plus-end tracking (+TIP) microtubule (MT)-associated protein family. G2L1 coordinates cooperativity between MTs and actin and was recently detected in an adipocyte CLASP2 interactome. Since CLASP2 has been linked to insulin action, and both actin and MTs play an unknown role in insulin action, we chose to study G2L1 within 3T3-L1 adipocytes by performing the first-ever G2L1 interactome. Using a commercially available antibody for G2L1 and two antibodies for epitope-tagged, overexpressed G2L1, we performed multiple affinity purification coupled with mass spectrometry experiments in combination with label-free quantitative proteomics and analysed the data with the bioinformatics tool Significance Analysis of Interactome. In concordance with findings in other cell types, we discovered that G2L1 co-IPs the master integrators of +TIP assembly, the end-binding (EB) proteins, with a strong preference for EB1 over EB3 in adipocytes. Subsequent EB1 interactome analysis confirmed reciprocal co-IP of G2L1. We discovered that G2L1 co-IPs the interaction partners CLASP2 and CLIP2, both of which are also +TIP family members, data which was confirmed by IP and western blot. Real-time total internal reflection fluorescence microscopy revealed colocalization of G2L1 and CLASP2 in adipocytes at growing MT ends. Since CLASP2 undergoes insulin-regulated phosphorylation in adipocytes, we hypothesized that the G2L1/CLIP2/EB1 network of +TIPs are also candidates for involvement in insulin-regulated control of MT dynamics. Using targeted quantitative phosphoproteomics, we discovered that insulin stimulates the phosphorylation of G2L1 at Ser597/599, CLIP2 at Ser552, and EB1 at Ser155. This now expands the novel network of insulin-affected +TIP family members to CLASP2, G2L1, CLIP2, and EB1 and introduces the new hypothesis that a coordinated network of MT-associated proteins cooperate to mediate insulin-regulated MT dynamics.

Disclosure
N.K. Barker: None. J.L. Krantz: None. S. Parker: None. G. Mouneimne: None. P.R. Langlais: None.
Regulation of Hepatic Insulin Sensitivity and Hepatic Steatosis by ULK1
Authors: KOO YOUNGDO , GARNEAU MICHAEL P. , ZHANG QUANJIANG , DALE ABEL E. 
Published: June 2018

Hepatic insulin resistance (IR) plays a central role in the pathophysiology of impaired glucose tolerance, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), which is emerging as a major cause of liver failure and hepatocellular carcinoma. Impaired autophagy may also contribute to hepatic insulin resistance, but the interactions between insulin sensitivity and autophagy are incompletely understood. The Unc-51 Like Autophagy Activating Kinase 1 (ULK1) is an early stage autophagosome formation related kinase that is activated in selective autophagy and may be independent of nutrient or energy status. We observed that in addition to its role in autophagy regulation, ULK1 may also directly regulate insulin signaling by modulating AKT dephosphorylation. Specifically, silencing ULK1 significantly impairs insulin-stimulated activation of AKT and GSK3β in hepatocytes in the absence of significant changes in autophagy. To understand the role of ULK1 in hepatic insulin action ULK1 liver specific knock-out mice were generated. Body weight increased in L-ULK1KO relative to wild type mice on normal chow diet or 60% high fat diet. L-ULK1 KO mice exhibited impaired glucose tolerance and insulin resistance. Serum concentrations of insulin, triglyceride, cholesterol, AST and ALT were increased. Phosphorylation levels of FOXO1 and FOXO3a were decreased in concert with increased expression levels of PEPCK and G6pase and increased hepatic glucose production. In contrast, L-ULK2 KO mice were phenotypically normal. Thus, ULK1 independently and directly regulates hepatic insulin sensitivity and glucose homeostasis.

Disclosure
Y. Koo: None. M.P. Garneau: None. Q. Zhang: None. E. Abel: None.
Liver-Specific Overexpression of 17ß-HSD13 Causes Hepatic Steatosis in Mice
Authors: SU WEN , GUAN YOUFEI 
Published: June 2018

According to our previous study, considerable evidences showed that a liver lipid droplet-associated protein 17β-HSD13 contribute to the development of liver disease. To understand the basis for this, we generated and studied transgenic mice that express human hsd17b13 specifically in hepatocytes (L-h17B13 mice).We examined the hepatic expression of several genes involved in fatty acid synthesis and oxidation in L-h17B13 mice. mRNA levels of three enzymes involved in fatty acid synthesis (SREBP-1c, fatty acid synthase [FAS], and ACC) were significantly increased L-h17B13 mice. The mRNA levels of peroxisome proliferator-activated receptor α (PPARα), a transcription factor that promotes fatty acid oxidation and its target gene, acyl-CoA oxidase (ACOX) and medium-chain acyl-CoA dehydrogenase (MCAD), also higher in L-h17B13 mice. mRNA levels of carnitine palmitoyltransferase (CPT1a), a protein involved in translocating fatty acids into the mitochondria for oxidation, was higher in L-h17B13 mice. ApoB, a lipid secretion related gene, was markedly reduced in L-h17B13 mice. Strikingly, male liver-specific h17β-HSD13 mice fed a standard chow diet display significantly elevated hepatic triglyceride levels at 3-4 months of age compared to matched littermate controls. When mice were fed a high-fat diet, this hepatic phenotype, as well as other metabolic phenotypes (obesity and glucose intolerance), worsened. Our investigations establish that 17β-HSD13 specifically overexpressed in mice hepatocytes induces hepatic steatosis and metabolic disorders.

Disclosure
W. Su: None. Y. Guan: None.