Overexpression of APOC1 in obob mice leads to hepatic steatosis and severe hepatic insulin resistance (2004)

Obese obob mice with strong overexpression of the human apolipoprotein C1 (APOC1) exhibit excessive free fatty acid (FFA) and triglyceride (TG) levels and severely reduced body weight (due to the absence of subcutaneous adipose tissue) and skin abnormalities. To evaluate the effects of APOC1 overexpression on hepatic and peripheral insulin sensitivity in a less-extreme model, we generated obob mice with mild overexpression of APOC1 (obob/APOC1+/−) and performed hyperinsulinemic clamp analysis. Compared with obob littermates, obob/APOC1+/− mice showed reduced body weight (−25%) and increased plasma levels of TG (+632%), total cholesterol (+134%), FFA (+65%), glucose (+73%, and insulin (+49%). Hyperinsulinemic clamp analysis revealed severe whole-body and hepatic insulin resistance in obob/APOC1+/− mice and, in addition, increased hepatic uptake of FFA and hepatic TG content. Treatment of obob/APOC1+/− mice with rosiglitazone strongly improved whole-body insulin sensitivity as well as hepatic insulin sensitivity, despite a further increase of hepatic fatty acid (FA) uptake and a panlobular increase of hepatic TG accumulation.We conclude that overexpression of APOC1 prevents rosiglitazone-induced peripheral FA uptake leading to severe hepatic steatosis. Interestingly, despite rosiglitazone-induced hepatic steatosis, hepatic insulin sensitivity improves dramatically. We hypothesize that the different hepatic fat accumulation and/or decrease in FA intermediates has a major effect on the insulin sensitivity of the liver. Obese obob mice with strong overexpression of the human apolipoprotein C1 (APOC1) exhibit excessive free fatty acid (FFA) and triglyceride (TG) levels and severely reduced body weight (due to the absence of subcutaneous adipose tissue) and skin abnormalities. To evaluate the effects of APOC1 overexpression on hepatic and peripheral insulin sensitivity in a less-extreme model, we generated obob mice with mild overexpression of APOC1 (obob/APOC1+/−) and performed hyperinsulinemic clamp analysis. Compared with obob littermates, obob/APOC1+/− mice showed reduced body weight (−25%) and increased plasma levels of TG (+632%), total cholesterol (+134%), FFA (+65%), glucose (+73%, and insulin (+49%). Hyperinsulinemic clamp analysis revealed severe whole-body and hepatic insulin resistance in obob/APOC1+/− mice and, in addition, increased hepatic uptake of FFA and hepatic TG content. Treatment of obob/APOC1+/− mice with rosiglitazone strongly improved whole-body insulin sensitivity as well as hepatic insulin sensitivity, despite a further increase of hepatic fatty acid (FA) uptake and a panlobular increase of hepatic TG accumulation. We conclude that overexpression of APOC1 prevents rosiglitazone-induced peripheral FA uptake leading to severe hepatic steatosis. Interestingly, despite rosiglitazone-induced hepatic steatosis, hepatic insulin sensitivity improves dramatically. We hypothesize that the different hepatic fat accumulation and/or decrease in FA intermediates has a major effect on the insulin sensitivity of the liver. The human apolipoprotein C1 (APOC1) gene is predominantly expressed in the liver and adipose tissue (1Lauer S.J. Walker D. Elshourbagy N.A. Reardon C.A. Levy-Wilson B. Taylor J.M. Two copies of the human apolipoprotein C-I gene are linked closely to the apolipoprotein E gene.J. Biol. Chem. 1988; 263: 7277-7286Abstract Full Text PDF PubMed Google Scholar). APOC1 is secreted as a 6.6 kDa protein in plasma, where it resides on chylomicrons, VLDLs, and HDLs (2Shulman R.S. Herbert P.N. Wehrly K. Fredrickson D.S. The complete amino acid sequence of C-I (apoLp-Ser), an apolipoprotein from human very low density lipoproteins.J. Biol. Chem. 1975; 250: 182-190Abstract Full Text PDF PubMed Google Scholar). To elucidate the role of APOC1 in lipid metabolism, we have previously generated transgenic mice overexpressing human APOC1 (3Jong M.C. Dahlmans V.E. van Gorp P.J. van Dijk K.W. Breuer M.L. Hofker M.H. Havekes L.M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.J. Clin. Invest. 1996; 98: 2259-2267Crossref PubMed Scopus (101) Google Scholar). Overexpression of human APOC1 in these mice is found predominantly in the liver and to a lesser degree in the skin and adipose tissue (4Jong M.C. Gijbels M.J. Dahlmans V.E. Gorp P.J. Koopman S.J. Ponec M. Hofker M.H. Havekes L.M. Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1.J. Clin. Invest. 1998; 101: 145-152Crossref PubMed Scopus (132) Google Scholar). Homozygous overexpressing APOC1 mice have strongly elevated levels of plasma total cholesterol (TC) and triglyceride (TG) due to the inhibitory action of APOC1 on VLDL uptake via hepatic receptors, in particular the LDL receptor-related protein (LRP) (3Jong M.C. Dahlmans V.E. van Gorp P.J. van Dijk K.W. Breuer M.L. Hofker M.H. Havekes L.M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.J. Clin. Invest. 1996; 98: 2259-2267Crossref PubMed Scopus (101) Google Scholar). In addition, homozygous APOC1 mice exhibit elevated plasma free fatty acid (FFA) concentrations (4Jong M.C. Gijbels M.J. Dahlmans V.E. Gorp P.J. Koopman S.J. Ponec M. Hofker M.H. Havekes L.M. Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1.J. Clin. Invest. 1998; 101: 145-152Crossref PubMed Scopus (132) Google Scholar). Another striking observation was the strong reduction in body weight and adipose tissue mass in these APOC1-overexpressing mice on an obob background, due to diminished net uptake of FFA into adipose tissue (5Jong M.C. Voshol P.J. Muurling M. Dahlmans V.E. Romijn J.A. Pijl H. Havekes L.M. Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1.Diabetes. 2001; 50: 2779-2785Crossref PubMed Scopus (80) Google Scholar). Thus, homozygous APOC1 overexpression in mice impairs peripheral FFA metabolism and adipose tissue development, and, as a consequence, APOC1 may be involved in the pathophysiology of insulin resistance. However, these homozygous APOC1 mice are an extreme model, because subcutaneous fat is totally absent and, in addition, they exhibit severe skin abnormalities, e.g., scaly skin and hair loss (4Jong M.C. Gijbels M.J. Dahlmans V.E. Gorp P.J. Koopman S.J. Ponec M. Hofker M.H. Havekes L.M. Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1.J. Clin. Invest. 1998; 101: 145-152Crossref PubMed Scopus (132) Google Scholar). Therefore, to study the effect of APOC1 overexpression on tissue-specific insulin sensitivity in a less-extreme model, we used mildly APOC1-overexpressing (heterozygous) mice on an obob background (obob/APOC1+/−). In obob mice, mild overexpression of human APOC1 results in slightly reduced body weight. Concomitantly with increased hepatic FFA uptake in obob/APOC1+/− mice, we observed hepatic steatosis and severe hepatic insulin resistance. In these mice, rosiglitazone treatment restored hepatic insulin sensitivity, despite a further increase in hepatic FFA uptake and increased steatosis. Rosiglitazone induced a different localization of the hepatic steatosis. We hypothesize that the different hepatic fat accumulation and/or decrease in fatty acid (FA) intermediates has a major effect on the insulin sensitivity of the liver. Transgenic mice with high expression of human APOC1 in the liver (line 11/1) were previously generated in our laboratory (3Jong M.C. Dahlmans V.E. van Gorp P.J. van Dijk K.W. Breuer M.L. Hofker M.H. Havekes L.M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.J. Clin. Invest. 1996; 98: 2259-2267Crossref PubMed Scopus (101) Google Scholar, 4Jong M.C. Gijbels M.J. Dahlmans V.E. Gorp P.J. Koopman S.J. Ponec M. Hofker M.H. Havekes L.M. Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1.J. Clin. Invest. 1998; 101: 145-152Crossref PubMed Scopus (132) Google Scholar) and further bred on a C57BL/6J background. Heterozygous ob/OB mice on a C57BL/6J background, obtained from the Jackson Laboratories, were intercrossed with heterozygous APOC1 transgenic mice (APOC1+/−) to obtain wild-type and APOC1+/− mice on an obob background (obob and obob/APOC1+/−, respectively). Mice were genotyped by PCR procedure and housed in a temperature-controlled room on a 12 h light/dark cycle with free access to water and standard mouse/rat chow [7.2 wt/wt % crude fat (corn oil), 24.4 wt/wt % crude protein, and 41.8% wt/wt carbohydrates (corn starch)] diet. At age 3–4 months, mice were housed individually. Body weight was measured weekly during the study. The study was approved by the institution's animal welfare committee, following Dutch guidelines for using laboratory animals. Three-month-old obob and obob/APOC1+/− mice were subjected to a pair-feeding regime. During the pair-feeding period, mice received 4.0 g of chow diet during the first 4 weeks, followed by 4.5 g for 8 weeks. During the pair-feeding period, body weight was measured weekly. To measure plasma parameters, blood was taken from the mice by tail bleeding after a 4 h fast. The blood was collected in paraoxinized tubes (to prevent hydrolysis of TGs) (6Zambon A. Hashimoto S.I. Brunzell J.D. Analysis of techniques to obtain plasma for measurement of levels of free fatty acids.J. Lipid Res. 1993; 34: 1021-1028Abstract Full Text PDF PubMed Google Scholar) and kept on ice. Subsequently, the samples were spun (13,000 rpm) at 4°C for 3 min, and the separated plasma was immediately assayed for TG, FFAs, ketone bodies, TC, and glucose. The remaining plasma was frozen in liquid nitrogen and stored at −20°C for later measurement of insulin. Levels of TG (corrected for free glycerol) and TC were determined by using commercially available enzymatic kits (#2336691, Boehringer Mannheim GmbH, Mannheim, Germany; and GPO-trinder kit 337-B, Sigma, St. Louis, MO). FFA was measured enzymaticaly with a NEFA-C kit (Wako Chemicals GmbH, Germany). Ketone bodies were determined by measuring β-hydroxybutyrate, using a commercially available enzymatic kit (#310-A, Sigma Diagnostics, Inc., St. Louis, MO). Plasma glucose was determined by a commercially available kit (#315-500, Sigma Diagnostics, Inc.). Insulin levels were measured by using a radioimmunoassay kit (Sensitive Rat Insulin Assay, Linco Research Inc., St. Charles, MO). Whole-body insulin sensitivity was measured by hyperinsulinemic clamp analysis. During the clamp analysis, whole-body glucose uptake and hepatic glucose production (HGP) were determined using [3H]d-glucose, (Amersham, Little Chalfont, UK). The clamp experiments were performed as described earlier (7Voshol P.J. Jong M.C. Dahlmans V.E. Kratky D. Levak-Frank S. Zechner R. Romijn J.A. Havekes L.M. In muscle-specific lipoprotein lipase-overexpressing mice, muscle triglyceride is increased of whole-body and muscle-specific glucose 2001; 50: PubMed Scopus Google Scholar). At the of the hyperinsulinemic clamp analysis of a of was to measure tissue-specific uptake of after the blood was collected and the animal was and adipose tissue and and subcutaneous fat were frozen in liquid and kept at −20°C for analysis. The collected blood was used to measure plasma and uptake and were as described by Voshol (7Voshol P.J. Jong M.C. Dahlmans V.E. Kratky D. Levak-Frank S. Zechner R. Romijn J.A. Havekes L.M. In muscle-specific lipoprotein lipase-overexpressing mice, muscle triglyceride is increased of whole-body and muscle-specific glucose 2001; 50: PubMed Scopus Google Scholar). In the of glucose the of glucose The was as the of the of to the plasma The was as the the of glucose and the of glucose The whole-body insulin sensitivity was as the of the in whole-body glucose uptake to the in plasma insulin levels from to hyperinsulinemic The hepatic insulin sensitivity was as the of the of during the hyperinsulinemic to the in plasma insulin To the uptake of by the tissue samples were in water protein was measured to the of measurement with Biol. Chem. Full Text PDF PubMed Google using as To the uptake of in and were by a of the of and of total lipid and Scholar). revealed that of the was in the FFA of was as uptake by the tissue of total tissue protein and for plasma FFA levels by the uptake of by the plasma FFA levels measured during the clamp TG and was determined in of and from the were and separated by as described previously L.M. free cholesterol in is available for of PubMed Scopus Google Scholar). of the was performed by the and the density using Germany). To hepatic steatosis, frozen were and hepatic was by were into that were for body weight. received the chow rosiglitazone a of During body weight was measured Plasma levels of TG, TC, and ketone bodies were measured after of whole-body glucose and tissue-specific uptake of FA were measured hyperinsulinemic clamp in mice that were for weeks. were performed as analysis, was The for samples was used to the of The for was at mice were increased plasma TG, TC, and FFA with obob In addition, plasma levels of glucose and insulin were elevated in obob/APOC1+/− mice, in insulin rosiglitazone treatment in obob/APOC1+/− mice in plasma TG Rosiglitazone treatment in obob/APOC1+/− mice showed a of the with plasma insulin with levels of TG, TC, and insulin of obob mice, obob/APOC1+/− mice, and obob/APOC1+/− mice obob mice mice obob mice obob mice obob mice mice obob mice TC, total free fatty mice obob mice in a TG, TC, total free fatty At 4 to of obob/APOC1+/− mice showed body weight and adipose tissue with obob were observed in subcutaneous fat weight mice and obob The in body weight obob and obob/APOC1+/− mice was due to because of 4.5 g chow for a of 12 in the in body weight obob and obob/APOC1+/− mice Rosiglitazone treatment in obob/APOC1+/− mice in increased body in weight and subcutaneous and adipose tissue of obob mice, obob/APOC1+/− mice, and obob/APOC1+/− weight mice obob mice adipose tissue of body adipose tissue of body mice obob mice obob mice in a To the severe and were due to insulin a hyperinsulinemic clamp analysis was 3 plasma and FA levels determined at the of the clamp Plasma glucose and insulin levels were different obob/APOC1+/− and obob mice during the clamp obob/APOC1+/− mice showed plasma glucose and insulin levels during the clamp with obob/APOC1+/− and obob mice Plasma FFA increased in and obob/APOC1+/− mice with obob mice showed severe whole-body insulin as by the insulin sensitivity with obob The results of wild-type mice are to that obob and obob/APOC1+/− mice are insulin in our using a insulin Whole-body glucose uptake increase during in obob/APOC1+/− mice with a increase in obob obob/APOC1+/− mice showed complete hepatic insulin because was of the during the clamp The rosiglitazone improved whole-body as well as hepatic insulin sensitivity in obob/APOC1+/− mice, with and FFA levels measured at the of the clamp mice obob mice obob mice obob mice obob in a To obtain into a of the severe hepatic insulin resistance in obob/APOC1+/− mice, we measured hepatic FA uptake during the hyperinsulinemic clamp and determined hepatic TG mice showed a increased hepatic FA uptake with obob increased hepatic FA in obob/APOC1+/− mice was with an increased hepatic TG accumulation with obob levels were increased in obob/APOC1+/− mice with obob protein protein, rosiglitazone treatment increased hepatic insulin sensitivity in obob/APOC1+/− mice, hepatic FA uptake and hepatic TG were with decrease with rosiglitazone treatment in obob/APOC1+/− mice protein In addition, we found that plasma ketone bodies were increased in obob/APOC1+/− mice rosiglitazone treatment with littermates, with the increased hepatic FA FFA and TG are involved in the pathophysiology of insulin resistance in Overexpression of human APOC1 whole-body FA and TG metabolism and adipose tissue APOC1 as in homozygous APOC1 mice, is an extreme with complete loss of subcutaneous adipose tissue mass and severe skin Thus, to study the effect of APOC1 on the pathophysiology of insulin resistance we the effects of (heterozygous) overexpression of human APOC1 in obob mice Compared with obob mice, obob/APOC1+/− mice strongly elevated levels of plasma TG, and are in with previously for homozygous APOC1-overexpressing mice on an obob background (5Jong M.C. Voshol P.J. Muurling M. Dahlmans V.E. Romijn J.A. Pijl H. Havekes L.M. Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1.Diabetes. 2001; 50: 2779-2785Crossref PubMed Scopus (80) Google Scholar). The observed be by of the uptake of by the liver via the LDL and (3Jong M.C. Dahlmans V.E. van Gorp P.J. van Dijk K.W. Breuer M.L. Hofker M.H. Havekes L.M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.J. Clin. Invest. 1996; 98: 2259-2267Crossref PubMed Scopus (101) Google Scholar). In addition, Jong (3Jong M.C. Dahlmans V.E. van Gorp P.J. van Dijk K.W. Breuer M.L. Hofker M.H. Havekes L.M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.J. Clin. Invest. 1996; 98: 2259-2267Crossref PubMed Scopus (101) Google Scholar) have that strong APOC1 overexpression of VLDL to the VLDL receptor, is to as a protein for lipoprotein A. S. H. The role of the very low density lipoprotein in the metabolism of plasma lipoproteins PubMed Scopus Google Scholar) and of FFA to as adipose leading to adipose tissue The the FFA uptake in APOC1-overexpressing mice at the In to the VLDL receptor, the action of FA as and may be by that APOC1 is to FFA tissue uptake with the FA with mice showed reduced uptake of FA in and adipose APOC1 to FA uptake in (5Jong M.C. Voshol P.J. Muurling M. Dahlmans V.E. Romijn J.A. Pijl H. Havekes L.M. Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1.Diabetes. 2001; 50: 2779-2785Crossref PubMed Scopus (80) Google Scholar). In addition, it is that to VLDL in a free in plasma, is to uptake by peripheral In the we that mild overexpression of APOC1 to mildly reduced body with obob littermates, is in with our study (5Jong M.C. Voshol P.J. Muurling M. Dahlmans V.E. Romijn J.A. Pijl H. Havekes L.M. Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1.Diabetes. 2001; 50: 2779-2785Crossref PubMed Scopus (80) Google Scholar). In with the body weight observed in obob/APOC1+/− mice was due to reduced fat weight. To a role of in body weight in these obob/APOC1+/− mice, we to our obob/APOC1+/− mice and obob g of chow diet During the 12 of the body weight the that human APOC1 overexpression has effects on adipose tissue of by the VLDL is by P.J. Dahlmans V.E. Gijbels M.J. van Dijk K.W. Havekes L.M. Jong M.C. Protection from obesity in mice the VLDL Biol. 2001; PubMed Scopus Google Scholar) showed adipose tissue with in VLDL mice, in body weight with wild-type and net FFA uptake in adipose tissue was in APOC1-overexpressing mice (5Jong M.C. Voshol P.J. Muurling M. Dahlmans V.E. Romijn J.A. Pijl H. Havekes L.M. Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1.Diabetes. 2001; 50: 2779-2785Crossref PubMed Scopus (80) Google Scholar). Interestingly, obob/APOC1+/− mice revealed severe with of severe insulin resistance and Hyperinsulinemic clamp using as a showed severe whole-body and hepatic insulin resistance in obob/APOC1+/− mice with obob an was increased in obob/APOC1+/− mice, with obob Thus, the increased and the of insulin to in with the whole-body insulin the observed severe in the obob/APOC1+/− have that is the of plasma glucose concentrations during metabolism in and Biol. PubMed Scopus Google Scholar, J.A. blood glucose by hepatic glucose production in Full Text PDF PubMed Scopus Google Scholar, M.C. of hepatic glucose 1998; PubMed Scopus Google Scholar). We on a the peripheral FA uptake and whole-body insulin resistance. The mild overexpression of APOC1 may have effects on adipose tissue FA uptake 8 in obob/APOC1+/− mice and obob to be by the observation that fat weight was in obob/APOC1+/− In muscle FA uptake be at in these mildly overexpressing obob/APOC1+/− using different animal have an hepatic insulin resistance and increased hepatic FA uptake and hepatic steatosis H. C.A. A. fatty hepatic insulin a role for protein PubMed Scopus Google Scholar, K. M. FFA hepatic insulin resistance by insulin of PubMed Scopus Google Scholar, A. S. A. H. accumulation in the liver is with in insulin of glucose production and free fatty of obesity in Clin. 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PubMed Scopus Google Scholar). rosiglitazone treatment in obob/APOC1+/− mice to a further increase in hepatic TG peripheral FA uptake is due to APOC1 overexpression in an increased FA to the liver was in obob/APOC1+/− The rosiglitazone-induced increase in TG was with a to lipid accumulation the liver increased steatosis was by increased hepatic insulin sensitivity, by the of insulin to during the hyperinsulinemic clamp analysis. may that the rosiglitazone-induced hepatic of TG accumulation is with insulin resistance. In rosiglitazone FA and M. M. K. B. B. Rosiglitazone a liver effects in Lipid Res. Full Text Full Text PDF PubMed Google leading to a reduction in intermediates J.M. B. P.J. K. fatty liver and insulin action in in the absence of PubMed Scopus Google Scholar). 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Romijn J.A. hepatic insulin sensitivity with hepatic triglyceride in PubMed Scopus Google Scholar) showed improved hepatic insulin sensitivity with plasma levels in In we showed that human APOC1 overexpression in mice FA to adipose tissue and to increased FA to the liver. increase in liver FA with hepatic steatosis by severe hepatic insulin resistance in the human APOC1-overexpressing Interestingly, hepatic insulin sensitivity, increased FA the with increased hepatic steatosis. rosiglitazone induced a different localization of the hepatic steatosis, we hypothesize that the different hepatic fat accumulation and/or decrease in FA intermediates has a major effect on the insulin sensitivity of the liver. The are to for to the hepatic The described in was by the for Research