scholarly journals Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice

2020 ◽  
Vol 61 (12) ◽  
pp. 1565-1576 ◽  
Author(s):  
Abudukadier Abulizi ◽  
Daniel F. Vatner ◽  
Zhang Ye ◽  
Yongliang Wang ◽  
Joao-Paulo Camporez ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Plasma Membrane ◽  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
Lipid Droplet ◽  
Microsomal Triglyceride Transfer Protein ◽  
Hepatic Insulin Resistance ◽  
Hepatic Insulin Sensitivity ◽  
Hepatic Insulin Signaling ◽  
Ceramide Content

Microsomal triglyceride transfer protein (MTTP) deficiency results in a syndrome of hypolipidemia and accelerated NAFLD. Animal models of decreased hepatic MTTP activity have revealed an unexplained dissociation between hepatic steatosis and hepatic insulin resistance. Here, we performed comprehensive metabolic phenotyping of liver-specific MTTP knockout (L-Mttp−/−) mice and age-weight matched wild-type control mice. Young (10–12-week-old) L-Mttp−/− mice exhibited hepatic steatosis and increased DAG content; however, the increase in hepatic DAG content was partitioned to the lipid droplet and was not increased in the plasma membrane. Young L-Mttp−/− mice also manifested normal hepatic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamps, no PKCε activation, and normal hepatic insulin signaling from the insulin receptor through AKT Ser/Thr kinase. In contrast, aged (10-month-old) L-Mttp−/− mice exhibited glucose intolerance and hepatic insulin resistance along with an increase in hepatic plasma membrane sn-1,2-DAG content and PKCε activation. Treatment with a functionally liver-targeted mitochondrial uncoupler protected the aged L-Mttp−/− mice against the development of hepatic steatosis, increased plasma membrane sn-1,2-DAG content, PKCε activation, and hepatic insulin resistance. Furthermore, increased hepatic insulin sensitivity in the aged controlled-release mitochondrial protonophore-treated L-Mttp−/− mice was not associated with any reductions in hepatic ceramide content. Taken together, these data demonstrate that differences in the intracellular compartmentation of sn-1,2-DAGs in the lipid droplet versus plasma membrane explains the dissociation of NAFLD/lipid-induced hepatic insulin resistance in young L-Mttp−/− mice as well as the development of lipid-induced hepatic insulin resistance in aged L-Mttp−/− mice.

Acute hepatic steatosis in mice by blocking β-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production

2005 ◽  
Vol 289 (3) ◽  
pp. G592-G598 ◽  
Author(s):  
Aldo Grefhorst ◽  
Jildou Hoekstra ◽  
Terry G. J. Derks ◽  
D. Margriet Ouwens ◽  
Julius F. W. Baller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Production Rate ◽  
Hepatic Steatosis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Pi3 Kinase ◽  
Hepatic Insulin Resistance ◽  
Nonesterified Fatty Acid ◽  
Hepatic Insulin Sensitivity

Accumulation of triglycerides (TG) in the liver is generally associated with hepatic insulin resistance. We questioned whether acute hepatic steatosis induced by pharmacological blockade of β-oxidation affects hepatic insulin sensitivity, i.e., insulin-mediated suppression of VLDL production and insulin-induced activation of phosphatidylinositol 3-kinase (PI3-kinase) and PKB. Tetradecylglycidic acid (TDGA), an inhibitor of carnitine palmitoyl transferase-1 (CPT1), was used for this purpose. Male C57BL/6J mice received 30 mg/kg TDGA or its solvent intraperitoneally and were subsequently fasted for 12 h. CPT1 inhibition resulted in severe microvesicular hepatic steatosis (19.9 ± 8.3 vs. 112.4 ± 25.2 nmol TG/mg liver, control vs. treated, P < 0.05) with elevated plasma nonesterified fatty acid (0.68 ± 0.25 vs. 1.21 ± 0.41 mM, P < 0.05) and plasma TG (0.39 ± 0.16 vs. 0.60 ± 0.10 mM, P < 0.05) concentrations. VLDL-TG production rate was not affected on CPT1 inhibition (74.9 ± 15.2 vs. 79.1 ± 12.8 μmol TG·kg−1·min−1, control vs. treated) although treated mice secreted larger VLDL particles (59.3 ± 3.6 vs. 66.6 ± 4.5 nm diameter, P < 0.05). Infusion of insulin under euglycemic conditions suppressed VLDL production rate in control and treated mice by 43 and 54%, respectively, with formation of smaller VLDL particles (51.2 ± 2.5 and 53.2 ± 2.8 nm diameter). Insulin-induced insulin receptor substrate (IRS)1- and IRS2-associated PI3-kinase activity and PKB-phosphorylation were not affected on TDGA treatment. In conclusion, acute hepatic steatosis caused by pharmacological inhibition of β-oxidation is not associated with reduced hepatic insulin sensitivity, indicating that hepatocellular fat content per se is not causally related to insulin resistance.

Effect of liver fat on insulin clearance

2007 ◽  
Vol 293 (6) ◽  
pp. E1709-E1715 ◽  
Author(s):  
Anna Kotronen ◽  
Satu Vehkavaara ◽  
Anneli Seppälä-Lindroos ◽  
Robert Bergholm ◽  
Hannele Yki-Järvinen
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Fat Content ◽  
Insulin Clearance ◽  
Liver Fat ◽  
Hepatic Insulin Resistance ◽  
Model Assessment ◽  
Liver Fat Content ◽  
Hepatic Insulin Sensitivity ◽  
Impaired Insulin

A fatty liver is associated with fasting hyperinsulinemia, which could reflect either impaired insulin clearance or hepatic insulin action. We determined the effect of liver fat on insulin clearance and hepatic insulin sensitivity in 80 nondiabetic subjects [age 43 ± 1 yr, body mass index (BMI) 26.3 ± 0.5 kg/m2]. Insulin clearance and hepatic insulin resistance were measured by the euglycemic hyperinsulinemic (insulin infusion rate 0.3 mU·kg−1·min−1for 240 min) clamp technique combined with the infusion of [3-3H]glucose and liver fat by proton magnetic resonance spectroscopy. During hyperinsulinemia, both serum insulin concentrations and increments above basal remained ∼40% higher ( P < 0.0001) in the high (15.0 ± 1.5%) compared with the low (1.8 ± 0.2%) liver fat group, independent of age, sex, and BMI. Insulin clearance (ml·kg fat free mass−1·min−1) was inversely related to liver fat content ( r = −0.52, P < 0.0001), independent of age, sex, and BMI ( r = −0.37, P = 0.001). The variation in insulin clearance due to that in liver fat (range 0–41%) explained on the average 27% of the variation in fasting serum (fS)-insulin concentrations. The contribution of impaired insulin clearance to fS-insulin concentrations increased as a function of liver fat. This implies that indirect indexes of insulin sensitivity, such as homeostatic model assessment, overestimate insulin resistance in subjects with high liver fat content. Liver fat content correlated significantly with fS-insulin concentrations adjusted for insulin clearance ( r = 0.43, P < 0.0001) and with directly measured hepatic insulin sensitivity ( r = −0.40, P = 0.0002). We conclude that increased liver fat is associated with both impaired insulin clearance and hepatic insulin resistance. Hepatic insulin sensitivity associates with liver fat content, independent of insulin clearance.

scholarly journals Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications

2019 ◽  
Vol 20 (9) ◽  
pp. 2109 ◽  
Author(s):  
Arulkumar Nagappan ◽  
Jooyeon Shin ◽  
Myeong Ho Jung
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
Cannabinoid Receptor ◽  
Inflammatory Responses ◽  
Hepatic Insulin Resistance ◽  
Leptin Resistance ◽  
Peripheral Tissues

Endogenous cannabinoids (ECs) are lipid-signaling molecules that specifically bind to cannabinoid receptor types 1 and 2 (CB1R and CB2R) and are highly expressed in central and many peripheral tissues under pathological conditions. Activation of hepatic CB1R is associated with obesity, insulin resistance, and impaired metabolic function, owing to increased energy intake and storage, impaired glucose and lipid metabolism, and enhanced oxidative stress and inflammatory responses. Additionally, blocking peripheral CB1R improves insulin sensitivity and glucose metabolism and also reduces hepatic steatosis and body weight in obese mice. Thus, targeting EC receptors, especially CB1R, may provide a potential therapeutic strategy against obesity and insulin resistance. There are many CB1R antagonists, including inverse agonists and natural compounds that target CB1R and can reduce body weight, adiposity, and hepatic steatosis, and those that improve insulin sensitivity and reverse leptin resistance. Recently, the use of CB1R antagonists was suspended due to adverse central effects, and this caused a major setback in the development of CB1R antagonists. Recent studies, however, have focused on development of antagonists lacking adverse effects. In this review, we detail the important role of CB1R in hepatic insulin resistance and the possible underlying mechanisms, and the therapeutic potential of CB1R targeting is also discussed.

Accretion of visceral fat and hepatic insulin resistance in pregnant rats

2008 ◽  
Vol 294 (2) ◽  
pp. E451-E455 ◽  
Author(s):  
Francine H. Einstein ◽  
Sigal Fishman ◽  
Radhika H. Muzumdar ◽  
Xiao Man Yang ◽  
Gil Atzmon ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Visceral Fat ◽  
Hepatic Glucose Production ◽  
Late Gestation ◽  
Hepatic Insulin Resistance ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Hepatic Insulin Sensitivity ◽  
In Pregnancy

Insulin resistance (IR) is a hallmark of pregnancy. Because increased visceral fat (VF) is associated with IR in nonpregnant states, we reasoned that fat accretion might be important in the development of IR during pregnancy. To determine whether VF depots increase in pregnancy and whether VF contributes to IR, we studied three groups of 6-mo-old female Sprague-Dawley rats: 1) nonpregnant sham-operated rats (Nonpreg; n = 6), 2) pregnant sham-operated rats (Preg; n = 6), and 3) pregnant rats in which VF was surgically removed 1 mo before mating (PVF−; n = 6). VF doubled by day 19 of pregnancy (Nonpreg 5.1 ± 0.3, Preg 10.0 ± 1.0 g, P < 0.01), and PVF− had similar amounts of VF compared with Nonpreg (PVF− 4.6 ± 0.8 g). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp in late gestation in chronically catheterized unstressed rats. Glucose IR (mg·kg−1·min−1) was highest in Nonpreg (19.4 ± 2.0), lowest in Preg (11.1 ± 1.4), and intermediate in PVF− (14.7 ± 0.6; P < 0.001 between all groups). During the clamp, Nonpreg had greater hepatic insulin sensitivity than Preg [hepatic glucose production (HGP): Nonpreg 4.5 ± 1.3, Preg 9.3 ± 0.5 mg·kg−1·min−1; P < 0.001]. With decreased VF, hepatic insulin sensitivity was similar to nonpregnant levels in PVF− (HGP 4.9 ± 0.8 mg·kg−1·min−1). Both pregnant groups had lower peripheral glucose uptake compared with Nonpreg. In parallel with hepatic insulin sensitivity, hepatic triglyceride content was increased in pregnancy (Nonpreg 1.9 ± 0.4 vs. Preg 3.2 ± 0.3 mg/g) and decreased with removal of VF (PVF− 1.3 ± 0.4 mg/g; P < 0.05). Accretion of visceral fat is an important component in the development of hepatic IR in pregnancy, and accumulation of hepatic triglycerides is a mechanism by which visceral fat may modulate insulin action in pregnancy.

scholarly journals OR17-01 Leptin Decreases De Novo Lipogenesis in Lipodystrophic Patients

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Annah Petek Baykal ◽  
Elizabeth J Parks ◽  
Robert Shamburek ◽  
Stephanie Chung ◽  
Majid M Syed-Abdul ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Mass Spectrometry Analysis ◽  
Alcoholic Fatty Liver ◽  
Peripheral Tissues ◽  
Hepatic Insulin Sensitivity ◽  
Total Body

Abstract De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). In rodent models of both health and lipodystrophy (LD), leptin decreases DNL. In human patients with LD, reduced adipose tissue results in adipokine deficiencies, including lower plasma leptin, which contributes to insulin resistance, dyslipidemia and ectopic accumulation of triglycerides (TG). The mechanisms by which leptin regulates serum and hepatic-TG are not well elucidated. Studying patients with LD before and after leptin therapy provides an important clinical model for understanding leptin’s effect on DNL. We hypothesized that leptin treatment in lipodystrophic patients would decrease DNL by decreasing insulin resistance and glycemia, resulting in reduced circulating and hepatic-TG. Leptin-naïve patients with LD (n=11) were treated with recombinant leptin (metreleptin) for 6 months. All measurements were performed after an 8–12 hr fast. The % of TG in TG-rich lipoproteins (TRLP-TG) derived from DNL (% DNL) was measured using body water labeling (oral D2O) of TG and mass spectrometry analysis. Absolute DNL was calculated as the product of TRLP-TG and % DNL. HbA1c and serum-TG were measured biochemically, hepatic-TG by MRI, and total body and hepatic insulin sensitivity measured during a hyperinsulinemic-euglycemic clamp. DNL decreased after metreleptin: % DNL from 22.8±6.8 to 9.1±5.1% (p=0.0008) and absolute DNL from 54.2±32.1 to 8.6±6.5 mg/dl (p=0.003). TRLP-TG decreased from (median [interquartile range]) 160 [107, 280] to 98 [66, 147] mg/dl (p=0.01). Total body and hepatic insulin sensitivity increased from 3.7 [3.0, 7.3] to 8.4 [5.1,10.6] mg/kgFFM/min (p=0.03) and from 61.0 [48.5, 69.3] to 84.7 [75.2, 107.6] % (p =0.01), respectively. HbA1c decreased from 8.6±1.8 to 7.1±1.4% (p=0.04), hepatic-TG decreased from 17.6±11.9 to 10.3±9.1% (p=0.02), and serum-TG from 386 [216, 686] to 223 [118, 497] mg/dl (p=0.06). DNL correlated negatively with insulin sensitivity both before (r=-0.73, p=0.03) and after (r=-0.85, p=0.004) metreleptin. DNL correlated positively with hepatic-TG before (r=0.70 p=0.03) and tended to correlate after metreleptin (r=0.65, p=0.06). The change in DNL correlated with change in serum-TG (r=0.77, p=0.04) but not the change in hepatic-TG (p=0.80). We show here for the first time that 6 months of metreleptin treatment in humans with LD decreased DNL by 84% and was associated with reductions in glycemia and improved peripheral and hepatic insulin sensitivity. These data indicate a strong link between metreleptin’s effects to increase clearance of blood glucose by peripheral tissues and reduce hepatic carbohydrate flux, resulting in DNL reductions. This led to lowered hepatic steatosis and dyslipidemia and suggests treatments that target multi-organ insulin resistance may lead to decreased NAFLD and cardiovascular risk.

Abstract 12189: Molecular Mechanisms Underlying Fasting Modulated Liver Insulin Sensitivity and Metabolism in Male Lipodystrophic Bscl2/Seipin-Deficient Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Weiqin Chen ◽  
Hongyi Zhou ◽  
Pradip Saha ◽  
Luge Li ◽  
Lawrence Chan
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Liver Lipid ◽  
De Novo Lipogenesis ◽  
Hepatic Insulin Signaling ◽  
A Cell

Bscl2–/– mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip Congenital Lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatomegly, hepatic steatosis and insulin resistance. The mechanisms that underlie hepatic steatosis and insulin resistance in Bscl2–/– mice are poorly understood. To address this issue, we performed hyperinsulinemic-euglycemic clamp on Bscl2–/– and wild-type mice after an overnight (16-h) fast, and found that Bscl2–/– actually displayed increased hepatic insulin sensitivity. Interestingly, liver in Bscl2–/– mice after a short term (4-h) fast had impaired acute insulin signaling, a defect that disappeared after a 16-h fast. Notably, fasting dependent hepatic insulin signaling in Bscl2–/– mice was not associated with liver diacylglyceride and ceramide contents, but could be attributable in part to the expression of hepatic insulin signaling receptor and substrates. Meanwhile, increased de novo lipogenesis and decreased β-oxidation led to severe hepatic steatosis in fed or short fasted Bscl2–/– mice while liver lipid accumulation and metabolism in Bscl2–/– mice was markedly impacted by prolonged fasting. Furthermore, mice with liver-specific inactivation of Bscl2 manifested no hepatic steatosis even under high fat diet, suggesting Bscl2 does not play a cell autonomous role in regulating liver lipid homeostasis. Overall, our results offered new insights into the metabolic adaptations of liver in response to fasting and uncovered a novel fasting-dependent regulation of hepatic insulin signaling in a mouse model of human BSCL2.

scholarly journals Short-Term Strength Exercise Reduces Hepatic Insulin Resistance in Obese Mice by Reducing PTP1B Content, Regardless of Changes in Body Weight

2021 ◽  
Vol 22 (12) ◽  
pp. 6402
Author(s):  
Kellen Cristina da Cruz Rodrigues ◽  
Rodrigo Martins Pereira ◽  
Guilherme Francisco Peruca ◽  
Lucas Wesley Torres Barbosa ◽  
Marcella Ramos Sant’Ana ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Hepatic Insulin Resistance ◽  
Strength Exercise ◽  
Term Strength ◽  
Obese Mice ◽  
Short Term ◽  
Hepatic Insulin Sensitivity ◽  
Short Term Strength

Obesity is closely related to insulin resistance and type 2 diabetes genesis. The liver is a key organ to glucose homeostasis since insulin resistance in this organ increases hepatic glucose production (HGP) and fasting hyperglycemia. The protein-tyrosine phosphatase 1B (PTP1B) may dephosphorylate the IR and IRS, contributing to insulin resistance in this organ. Aerobic exercise is a great strategy to increase insulin action in the liver by reducing the PTP1B content. In contrast, no study has shown the direct effects of strength training on the hepatic metabolism of PTP1B. Therefore, this study aims to investigate the effects of short-term strength exercise (STSE) on hepatic insulin sensitivity and PTP1B content in obese mice, regardless of body weight change. To achieve this goal, obese Swiss mice were submitted to a strength exercise protocol lasting 15 days. The results showed that STSE increased Akt phosphorylation in the liver and enhanced the control of HGP during the pyruvate tolerance test. Furthermore, sedentary obese animals increased PTP1B content and decreased IRS-1/2 tyrosine phosphorylation; however, STSE was able to reverse this scenario. Therefore, we conclude that STSE is an important strategy to improve the hepatic insulin sensitivity and HGP by reducing the PTP1B content in the liver of obese mice, regardless of changes in body weight.

Starch and β-glucan in a whole-grain-like structural form improve hepatic insulin sensitivity in diet-induced obese mice

2019 ◽  
Vol 10 (8) ◽  
pp. 5091-5101 ◽  
Author(s):  
Kaiyun Luo ◽  
Xufeng Wang ◽  
Genyi Zhang
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Hepatic Insulin Resistance ◽  
Obese Mice ◽  
Structural Form ◽  
Whole Grain ◽  
Hepatic Insulin Sensitivity

WGLSF improves hepatic insulin resistance and glucose homeostasis in diet-induced obese mice.

scholarly journals Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways

2013 ◽  
Vol 305 (1) ◽  
pp. E89-E100 ◽  
Author(s):  
Daniel F. Vatner ◽  
Dirk Weismann ◽  
Sara A. Beddow ◽  
Naoki Kumashiro ◽  
Derek M. Erion ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Thyroid Hormone ◽  
Hepatic Steatosis ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Hepatic Insulin Resistance ◽  
Lipid Lowering ◽  
Hepatic Insulin Sensitivity ◽  
Thyroid Hormone Receptor Β

Liver-specific thyroid hormone receptor-β (TRβ)-specific agonists are potent lipid-lowering drugs that also hold promise for treating nonalcoholic fatty liver disease and hepatic insulin resistance. We investigated the effect of two TRβ agonists (GC-1 and KB-2115) in high-fat-fed male Sprague-Dawley rats treated for 10 days. GC-1 treatment reduced hepatic triglyceride content by 75%, but the rats developed fasting hyperglycemia and hyperinsulinemia, attributable to increased endogenous glucose production (EGP) and diminished hepatic insulin sensitivity. GC-1 also increased white adipose tissue lipolysis; the resulting increase in glycerol flux may have contributed to the increase in EGP. KB-2115, a more TRβ- and liver-specific thyromimetic, also prevented hepatic steatosis but did not induce fasting hyperglycemia, increase basal EGP rate, or diminish hepatic insulin sensitivity. Surprisingly, insulin-stimulated peripheral glucose disposal was diminished because of a decrease in insulin-stimulated skeletal muscle glucose uptake. Skeletal muscle insulin signaling was unaffected. Instead, KB-2115 treatment was associated with a decrease in GLUT4 protein content. Thus, although both GC-1 and KB-2115 potently treat hepatic steatosis in fat-fed rats, they each worsen insulin action via specific and discrete mechanisms. The development of future TRβ agonists must consider the potential adverse effects on insulin sensitivity.

scholarly journals Inhibition of hepatic Niemann-Pick C1-like 1 improves hepatic insulin resistance

2009 ◽  
Vol 297 (5) ◽  
pp. E1030-E1038 ◽  
Author(s):  
Mitsunori Nomura ◽  
Hideto Ishii ◽  
Akio Kawakami ◽  
Masayuki Yoshida
Keyword(s):  
Insulin Resistance ◽  
Er Stress ◽  
Hepatic Steatosis ◽  
Hepatic Insulin Resistance ◽  
Ros Generation ◽  
Akt Activation ◽  
Hepatic Insulin Signaling ◽  
Niemann Pick ◽  
Jnk Activation

The present study attempted to define the role of hepatic Niemann-Pick C1-like 1 (NPC1L1), a cholesterol transporter, in hepatic insulin resistance as well as hepatic steatosis. The inhibition of NPC1L1 and its molecular consequences were examined in Zucker obese fatty (ZOF) rats and cultured steatotic hepatocytes using ezetimibe, a pharmacoloigcal inhibitor of NPC1L1, and short hairpin RNA (shRNA) of NPC1L1. Ezetimibe improved hepatic insulin signaling as well as hepatic steatosis in ZOF rats. It also restored insulin sensitivity in steatotic hepatocytes in vitro through a reduction in hepatic reactive oxygen species (ROS) generation, JNK activation, and ER stress. In addition, ezetimibe recovered insulin-induced Akt activation and reduced gluconeogenic genes in the liver of ZOF rats and cultured steatotic hepatocytes. Transfection of NPC1L1 shRNA into hepatocytes also reduced ROS generation and ER stress. These results indicate that NPC1L1 contributes to hepatic insulin resistance through cholesterol accumulation, and its inhibition could be a potential therapeutic target of hepatic insulin resistance.

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