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Although aging is associated with progressive adiposity and a decline in liver function, the underlying molecular mechanisms and metabolic interplay are incompletely understood. Here, we demonstrate that aging induces hepatic protein kinase Cbeta (PKCβ) expression, while hepatocyte PKCβ deficiency (PKCβ Hep-/- ) in mice significantly attenuates obesity in aged mice fed a high-fat diet. Compared with control PKCβ fl/fl mice, PKCβ Hep-/- mice showed elevated energy expenditure with augmentation of oxygen consumption and carbon dioxide production which was dependent on β3-adrenergic receptor signaling, thereby favoring negative energy balance. This effect was accompanied by induction of thermogenic genes in brown adipose tissue (BAT) and increased BAT respiratory capacity, as well as a shift to oxidative muscle fiber type with an improved mitochondrial function, thereby enhancing oxidative capacity of thermogenic tissues. Furthermore, in PKCβ Hep-/- mice, we determined that PKCβ overexpression in the liver mitigated elevated expression of thermogenic genes in BAT. In conclusion, our study thus establishes hepatocyte PKCβ induction as a critical component of pathophysiological energy metabolism by promoting progressive hepatic and extrahepatic metabolic derangements in energy homeostasis, contributing to late-onset obesity. These findings have potential implications for augmenting thermogenesis as a means of combating aging-induced obesity., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The hormone FGF21 regulates carbohydrate and lipid homeostasis as well as body weight, and increasing FGF21 improves metabolic abnormalities associated with obesity and diabetes. FGF21 is thought to act on its target tissues, including liver and adipose tissue, to improve insulin sensitivity and reduce adiposity. Here, we used mice with selective hepatic inactivation of the IR (LIRKO) to determine whether insulin sensitization in liver mediates FGF21 metabolic actions. Remarkably, hyperglycemia was completely normalized following FGF21 treatment in LIRKO mice, even though FGF21 did not reduce gluconeogenesis in these animals. Improvements in blood sugar were due in part to increased glucose uptake in brown fat, browning of white fat, and overall increased energy expenditure. These effects were preserved even after removal of the main interscapular brown fat pad. In contrast to its retained effects on reducing glucose levels, the effects of FGF21 on reducing circulating cholesterol and hepatic triglycerides and regulating the expression of key genes involved in cholesterol and lipid metabolism in liver were disrupted in LIRKO mice. Thus, FGF21 corrects hyperglycemia in diabetic mice independently of insulin action in the liver by increasing energy metabolism via activation of brown fat and browning of white fat, but intact liver insulin action is required for FGF21 to control hepatic lipid metabolism.

Objective: Chylomicron and very low-density lipoprotein remnants are cleared from the circulation in the liver by heparan sulfate proteoglycan (HSPG) receptors (syndecan-1), the low-density lipoprotein receptor (LDLR), and LDLR-related protein-1 (LRP1), but the relative contribution of each class of receptors under different dietary conditions remains unclear., Approach and Results: Triglyceride-rich lipoprotein clearance was measured in AlbCre(+)Ndst1(f/f), Ldlr(-/-), and AlbCre(+)Lrp1(f/f) mice and mice containing combinations of these mutations. Triglyceride measurements in single and double mutant mice showed that HSPGs and LDLR dominate clearance under fasting conditions and postprandial conditions, but LRP1 contributes significantly when LDLR is absent. Mice lacking hepatic expression of all 3 receptors (AlbCre(+)Ndst1(f/f) Lrp1(f/f) Ldlr(-/-)) displayed dramatic hyperlipidemia (870 ± 270 mg triglyceride/dL; 1300 ± 350 mg of total cholesterol/dL) and exhibited persistent elevated postprandial triglyceride levels because of reduced hepatic clearance. Analysis of the particles accumulating in mutants showed that HSPGs preferentially clear a subset of small triglyceride-rich lipoproteins (≈ 20-40 nm diameter), whereas LDLR and LRP1 clear larger particles (≈ 40-60 nm diameter). Finally, we show that HSPGs play a major role in clearance of triglyceride-rich lipoproteins in mice fed normal chow or under postprandial conditions but seem to play a less significant role on a high-fat diet., Conclusions: These data show that HSPGs, LDLR, and LRP1 clear distinct subsets of particles, that HSPGs work independently of LDLR and LRP1, and that HSPGs, LDLR, and LRP1 are the 3 major hepatic triglyceride-rich lipoprotein clearance receptors in mice.

Elevated plasma triglyceride levels represent a risk factor for premature atherosclerosis. In mice, accumulation of triglyceride-rich lipoproteins can occur if sulfation of heparan sulfate in hepatocytes is diminished, as this alters hepatic lipoprotein clearance via heparan sulfate proteoglycans (HSPGs). However, the relevant HSPG has not been determined. In this study, we found by RT-PCR analysis that mouse hepatocytes expressed the membrane proteoglycans syndecan-1, -2, and -4 and glypican-1 and -4. Analysis of available proteoglycan-deficient mice showed that only syndecan-1 mutants (Sdc1-/- mice) accumulated plasma triglycerides. Sdc1-/- mice also exhibited prolonged circulation of injected human VLDL and intestinally derived chylomicrons. We found that mice lacking both syndecan-1 and hepatocyte heparan sulfate did not display accentuated triglyceride accumulation compared with single mutants, suggesting that syndecan-1 is the primary HSPG mediating hepatic triglyceride clearance. Immunoelectron microscopy showed that syndecan-1 was expressed specifically on the microvilli of hepatocyte basal membranes, facing the space of Disse, where lipoprotein uptake occurs. Abundant syndecan-1 on wild-type murine hepatocytes exhibited saturable binding of VLDL and inhibition by heparin and facilitated degradation of VLDL. Furthermore, adenovirus-encoded syndecan-1 restored binding, uptake, and degradation of VLDL in isolated Sdc1-/- hepatocytes and the lipoprotein clearance defect in Sdc1-/- mice. These findings provide the first in vivo genetic evidence that syndecan-1 is the primary hepatocyte HSPG receptor mediating the clearance of both hepatic and intestinally derived triglyceride-rich lipoproteins.

We examined the role of hepatic heparan sulfate in triglyceride-rich lipoprotein metabolism by inactivating the biosynthetic gene GlcNAc N-deacetylase/N-sulfotransferase 1 (Ndst1) in hepatocytes using the Cre-loxP system, which resulted in an approximately 50% reduction in sulfation of liver heparan sulfate. Mice were viable and healthy, but they accumulated triglyceride-rich lipoprotein particles containing apoB-100, apoB-48, apoE, and apoCI-IV. Compounding the mutation with LDL receptor deficiency caused enhanced accumulation of both cholesterol- and triglyceride-rich particles compared with mice lacking only LDL receptors, suggesting that heparan sulfate participates in the clearance of cholesterol-rich lipoproteins as well. Mutant mice synthesized VLDL normally but showed reduced plasma clearance of human VLDL and a corresponding reduction in hepatic VLDL uptake. Retinyl ester excursion studies revealed that clearance of intestinally derived lipoproteins also depended on hepatocyte heparan sulfate. These findings show that under normal physiological conditions, hepatic heparan sulfate proteoglycans play a crucial role in the clearance of both intestinally derived and hepatic lipoprotein particles.