As a chronic metabolic syndrome, hyperlipidaemia is manifested as aberrantly elevated cholesterol and triglyceride (TG) levels, primarily attributed to disorders in lipid metabolism. Despite the promising outlook for hyperlipidaemia treatment, the need persists for the development of lipid-lowering agents with heightened efficiency and minimal toxicity. This investigation aims to elucidate the lipid-lowering effects and potential pharmacodynamic mechanisms of Anti-b, a novel low MW compound.

We employed high-fat diet (HFD) in hamsters and mice or oleic acid (OA) in cultures of HepG2 cells and LO2 cells to induce hyperlipidaemia models. We administered Anti-b to assess its therapeutic effects on dyslipidaemia and hepatic steatosis. We used western blotting, RNA sequencing, GO and KEGG analysis, oil red O staining, along with molecular docking and molecular dynamics simulation to elucidate the mechanisms underlying the effects of Anti-b.

Anti-b exhibited a substantial reduction in HFD-induced elevation of blood lipids, liver weight to body weight ratio, liver diameter and hepatic fat accumulation. Moreover, Anti-b demonstrated therapeutic effects in alleviating total cholesterol (TC), TG levels, and lipid accumulation derived from OA in HepG2 cells and LO2 cells. Mechanistically, Anti-b selectively bound to the mTOR kinase protein and increased mTOR thermal stability, resulting in downregulation of phosphorylation level. Notably, Anti-b exerted anti-hyperlipidaemia effects by modulating PPARγ and SREBP1 signalling pathways and reducing the expression level of mSREBP1 and PPARγ proteins.

In conclusion, our study has provided initial data of a novel low MW compound, Anti-b, designed and synthesised to target mTOR protein directly. Our results indicate that Anti-b may represent a novel class of drugs for the treatment of hyperlipidemia and hepatic steatosis.

Hepatic glycoprotein nonmetastatic melanoma protein B (GPNMB) and nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) play essential roles in lipid metabolism. This study aimed to examine the molecular mechanism through which PPARγ controls GPNMB expression in liver steatosis. A microarray database was used to examine the gene expression patterns associated with fatty liver in type 2 diabetic leptin-deficient (ob/ob) mice, as well as in patients with non-alcoholic fatty liver disease (NAFLD) and advanced NAFLD. GPNMB expression significantly increased in the fatty livers of humans and mice. Elevated Gpnmb expression was notably reduced by liver-specific Pparγ knockout (PPARγLKO) in ob/ob mice. Similarly, alcohol-fed mice had increased hepatic Gpnmb levels. Transcriptomic analysis of the human liver samples revealed that Gpnmb expression was markedly higher in patients with fatty liver diseases, including those with NAFLD and alcoholic fatty liver disease, than in controls. Reporter and electrophoretic mobility shift assays confirmed that PPARγ directly enhances Gpnmb transcription via three functional PPARγ-responsive elements within the first intron. In conclusion, these findings suggest that Gpnmb is a novel PPARγ target in liver steatosis.

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated fatty liver disease (MAFLD), is a leading cause of liver disease worldwide and can progress to cirrhosis and cancer. Despite its prevalence, the pathogenesis of MASH remains poorly understood, and there is only one U.S. Food and Drug Administration-approved treatment, highlighting the need for new therapeutic strategies. Peroxisome proliferator-activated receptor (PPAR)γ is activated in the liver under high-fat or obese conditions, promoting lipid storage and contributing to MASH progression. We found that USP28 expression is elevated in the livers of MAFLD/MASH patients. Through dietary induction, including a methionine-choline deficient (MCD) diet and a western diet (WD) combined with carbon tetrachloride (CCl4) injections, we established two severe mouse models of MASH to explore the role of USP28. Mechanistically, the hepatic deubiquitinase (DUB) USP28 directly binds to PPARγ, preventing its ubiquitination and subsequent degradation, thereby maintaining the integrity of the PPARγ signaling pathway. In the absence of Usp28 or if the DUB is inhibited, PPARγ is downregulated, and the PPAR signaling pathway is inhibited, enhancing cellular defenses against excess fat. Both genetic and pharmacological inactivation of Usp28 significantly reduced MASH severity induced by the MCD diet or WD-CCl4 regimen, as well as WD-CCl4-induced hepatocellular carcinoma in mice.

Dysregulation of lipid homeostasis pathway causes many liver diseases, including hepatic steatosis. One of the primary factors contributing to lipid accumulation is fatty acid uptake by the liver. Transmembrane protein 135 (TMEM135), which exists in mitochondria and peroxisomes, participates in intracellular lipid metabolism. This study aims to investigate the role of TMEM135 on regulating cellular lipid import in the liver.

We used in vivo, ex vivo, and in vitro models of steatosis. TMEM135 knockout (TMEM135KO) and wild type (WT) mice were fed a high-fat diet (HFD) to induce hepatic steatosis. Primary mouse hepatocytes and AML12 cells were treated with free fatty acid (FFA). Additionally, TMEM135-deficient stable cells and overexpressed cells were established using AML12 cells.

TMEM135 deficiency mitigated lipid accumulation in the liver of HFD-fed TMEM135KO mice. TMEM135-depleted primary hepatocytes and AML12 cells exhibited less lipid accumulation when treated with FFA compared to control cells, as shown as lipid droplets. Consistently, the effect of TMEM135 depletion on lipid accumulation was completely reversed under TMEM135 overexpression conditions. CD36 expression was markedly induced by HFD or FFA, which was reduced by TMEM135 depletion. Among the SIRT family proteins, only SIRT1 expression definitely increased in the liver of HFD-fed TMEM135KO mice along with a significant increase in NAD+/NADH ratio. However, inhibition of SIRT1 in TMEM135-depleted cells using siSIRT1 or the SIRT1 inhibitor EX-527 resulted in an increase of CD36 expression and consequent TG levels.

TMEM135 depletion attenuates CD36 expression in a SIRT1-dependent manner, thereby reducing cellular lipid uptake and hepatic steatosis.

Hu-lu-su-pian (HLSP) is an oral tablet derived from the active compounds of Cucumis melo L., a traditional Chinese medicine. This contemporary formulation is frequently employed in clinical settings for the management of liver ailments. However, the molecular mechanism by which HLSP affects metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study aimed to explore the therapeutic potential of HLSP on MASLD and the underlying mechanism.

The researchers used ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) to identify the primary chemical components of HLSP. A mouse model of MASLD induced by AKT was established through hydrodynamic transfection with activated forms of AKT. Serum biochemical indices and liver pathological assessments were employed to evaluate the pharmacodynamic effects of HLSP on MASLD. Transcriptomic analysis of the liver was conducted to detect differentially expressed genes (DEGs). Further examination of significant DEGs and proteins was performed using quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting, and immunohistochemistry (IHC) techniques, respectively. The efficacy and molecular mechanisms of HLSP in MASLD were further explored in HepG2 and Huh-7 cells in the presence of gene overexpression.

From the UPLC-Q-TOF-MS/MS results, we detected fifteen components from HLSP. From the results of serum biochemical indices and hepatic pathology analyses, it is clear that HLSP is effective in treating MASLD. The findings from hepatic transcription studies revealed CIDEA as an essential DEG that facilitates lipid droplet (LD) fusion and enhances de novo fatty acid synthesis from scratch in cases of hepatic steatosis, which HLSP has the potential to counteract. In addition, HLSP significantly reduced lipid accumulation and expression of critical genes for de novo fatty acid synthesis in HepG2 and Huh-7 cells overexpressing CIDEA.

The present study preliminarily suggests that HLSP can ameliorate hepatic steatosis by inhibiting CIDEA-mediated de novo fatty acid synthesis and LD formation, which may offer a potential strategy for treating MASLD.

The peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor abundantly expressed in the nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the mechanism by which PPARγ regulates the transmembrane and coiled-coil domain family 3 (Tmcc3) gene in the liver. We found that TMCC3 is highly expressed in the fatty liver of humans and mice with NAFLD and alcoholic fatty liver disease. Three exon 1 variants (Tmcc3-1a, -1b, and -1c) of mouse Tmcc3 were identified. TMCC3-1B was highly expressed in the fatty liver of type 2 diabetic ob/ob mice; however, this increase in expression was ameliorated by liver-specific knockout of PPARγ. Reporter assays and electrophoretic mobility shift assays showed that PPARγ positively regulates Tmcc3-1b and -1c transcription through the same PPARγ-responsive element present in the 5'-region of each Tmcc3. Altogether, our results indicate that Tmcc3 is a novel PPARγ target in the fatty liver disease.

Betaine is the major water-soluble component of Lycium chinensis. Although there are reports of a protective effect of betaine on fatty liver disease, the underlying mechanisms are unclear. We attempted to elucidate the molecular regulation of betaine on hyperglycemia-induced hepatic lipid accumulation via Forkhead box O (FoxO)6 activation. HepG2 cells and liver tissue isolated from db/db mice treated with betaine were used. The present study investigated whether betaine ameliorates hepatic steatosis by inhibiting FoxO6/peroxisome proliferator-activated receptor gamma (PPARγ) signaling in liver cells. Interestingly, betaine notably decreased lipid accumulation in tissues with FoxO6-induced mRNA expression of lipogenesis-related genes. Furthermore, betaine inhibited the FoxO6 interaction with PPARγ and cellular triglycerides in high-glucose- or FoxO6-overexpression-treated liver cells. In addition, we confirmed that betaine administration via oral gavage significantly ameliorated hepatic steatosis in db/db mice. We conclude that betaine ameliorates hepatic steatosis, at least in part, by inhibiting the interaction between FoxO6 and PPARγ, thereby suppressing lipogenic gene transcription.

LncRNAs are involved in modulating the individual risk and the severity of progression in metabolic dysfunction-associated fatty liver disease (MASLD), but their precise roles remain largely unknown. This study aimed to investigate the role of lncRNA Snhg3 in the development and progression of MASLD, along with the underlying mechanisms. The result showed that Snhg3 was significantly downregulated in the liver of high-fat diet-induced obesity (DIO) mice. Notably, palmitic acid promoted the expression of Snhg3 and overexpression of Snhg3 increased lipid accumulation in primary hepatocytes. Furthermore, hepatocyte-specific Snhg3 deficiency decreased body and liver weight, alleviated hepatic steatosis and promoted hepatic fatty acid metabolism in DIO mice, whereas overexpression induced the opposite effect. Mechanistically, Snhg3 promoted the expression, stability and nuclear localization of SND1 protein via interacting with SND1, thereby inducing K63-linked ubiquitination modification of SND1. Moreover, Snhg3 decreased the H3K27me3 level and induced SND1-mediated chromatin loose remodeling, thus reducing H3K27me3 enrichment at the Pparg promoter and enhancing PPARγ expression. The administration of PPARγ antagonist T0070907 improved Snhg3-aggravated hepatic steatosis. Our study revealed a new signaling pathway, Snhg3/SND1/H3K27me3/PPARγ, responsible for mice MASLD and indicates that lncRNA-mediated epigenetic modification has a crucial role in the pathology of MASLD.

Endoplasmic reticulum (ER) stress is a major cause of hepatic steatosis through increasing de novo lipogenesis. Forkhead box O6 (FoxO6) is a transcription factor mediating insulin signaling to glucose and lipid metabolism. Therefore, dysregulated FoxO6 is involved in hepatic lipogenesis. This study elucidated the role of FoxO6 in ER stress-induced hepatic steatosis in vivo and in vitro. Hepatic ER stress responses and β-oxidation were monitored in mice overexpressed with constitutively active FoxO6 allele and FoxO6-null mice. For the in vitro study, liver cells overexpressing constitutively active FoxO6 and FoxO6-siRNA were treated with high glucose, and lipid metabolism alterations were measured. ER stress-induced FoxO6 activation suppressed hepatic β-oxidation in vivo. The expression and transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) were significantly decreased in the constitutively active FoxO6 allele. Otherwise, inhibiting β-oxidation genes were reduced in the FoxO6-siRNA and FoxO6-KO mice. Our data showed that the FoxO6-induced hepatic lipid accumulation was negatively regulated by insulin signaling. High glucose treatment as a hyperglycemia condition caused the expression of ER stress-inducible genes, which was deteriorated by FoxO6 activation in liver cells. However, high glucose-mediated ER stress suppressed β-oxidation gene expression through interactions between PPARα and FoxO6 corresponding to findings in the in vivo study-lipid catabolism is also regulated by FoxO6. Furthermore, insulin resistance suppressed b-oxidation through the interaction between FoxO6 and PPARα promotes hepatic steatosis, which, due to hyperglycemia-induced ER stress, impairs insulin signaling. KEY MESSAGES: Our original aims were to delineate the interrelation between the regulation of PPARα and the transcription factor FoxO6 pathway in relation to lipid metabolism at molecular levels. Evidence on high glucose promoted FoxO6 activation induced lipid accumulation in liver cells. The effect of PPARα activation of the insulin signaling. FoxO6 plays a pivotal role in hepatic lipid accumulation through inactivation of PPARα in FoxO6-overexpression mice.

In pigs, meat quality depends markedly on the fatty acid (FA) content and composition of the intramuscular fat, which is partly determined by the gene expression in this tissue. The aim of this work was to identify the link between muscle gene expression and its FA composition. In an (Iberian × Duroc) × Duroc backcrossed pig population, we identified modules of co-expressed genes, and correlation analyses were performed for each of them versus the phenotypes, finding four relevant modules. Two of the modules were positively correlated with saturated FAs (SFAs) and monounsaturated FAs (MUFAs), while negatively correlated with polyunsaturated FAs (PUFAs) and the omega-6/omega-3 ratio. The gene-enrichment analysis showed that these modules had over-representation of pathways related with the biosynthesis of unsaturated FAs, the Peroxisome proliferator-activated receptor signalling pathway and FA elongation. The two other relevant modules were positively correlated with PUFA and the n-6/n-3 ratio, but negatively correlated with SFA and MUFA. In this case, they had an over-representation of pathways related with fatty and amino acid degradation, and with oxidative phosphorylation. Using a graphical Gaussian model, we inferred a network of connections between the genes within each module. The first module had 52 genes with 87 connections, and the most connected genes were ADIPOQ, which is related with FA oxidation, and ELOVL6 and FABP4, both involved in FA metabolism. The second module showed 196 genes connected by 263 edges, being FN1 and MAP3K11 the most connected genes. On the other hand, the third module had 161 genes connected by 251 edges and ATG13 was the top neighbouring gene, while the fourth module had 224 genes and 655 connections, and its most connected genes were related with mitochondrial pathways. Overall, this work successfully identified relevant muscle gene networks and modules linked with FA composition, providing further insights on how the physiology of the pigs influences FA composition.

One of the main causes of death on the globe is cancer. Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors, including PPARα, PPARδ and PPARγ, which are important in regulating cancer cell proliferation, survival, apoptosis, and tumor growth. Activation of PPARs by endogenous or synthetic compounds regulates tumor progression in various tissues. Although each PPAR isotype suppresses or promotes tumor development depending on the specific tissues or ligands, the mechanism is still unclear. PPARs are receiving interest as possible therapeutic targets for a number of disorders. Numerous clinical studies are being conducted on PPARs as possible therapeutic targets for cancer. Therefore, this review will focus on the existing and future uses of PPARs agonists and antagonists in treating malignancies. PubMed, Science Direct, and Scopus databases were searched regarding the effect of PPARs on various types of cancers until the end of May 2023. The results of the review articles showed the therapeutic influence of PPARs on a wide range of cancer on in vitro, in vivo and clinical studies. However, further experimental and clinical studies are needed to be conducted on the influence of PPARs on various cancers.

Coffee berry extracts are anti-lipogenic and lipolytic. This study aims to investigate the effect and mechanism of coffee pulp on high-fat diet (HFD)-induced glucose and lipid metabolism disorder in mice.

The type 2 diabetes (T2D) mouse model was established by feeding the C57BL/6 J mice with HFD. Mice were administered with coffee pulp diluted in drinking water before or after the establishment of the T2D mouse model. After treatment, the body weight and fasting blood glucose (FBG) of mice were monitored; the intraperitoneal glucose tolerance test (IPGTT) of mice was performed; plasma insulin was determined by ELISA; serum total cholesterol (TC), triglyceride (TG) and liver TG were determined by biochemical analysis; hematoxylin-eosin (H&E) staining was used to evaluate organ histomorphology. Gene expression of key genes in de novo lipogenesis (DNL) in the liver was examined by quantitative reverse transcription PCR (RT-qPCR).

Mice that consumed coffee pulp after modeling showed reduced FBG and liver TG, improved IPGTT, and alleviated fatty liver. Consuming coffee pulp before modeling prevented HFD-induced blood glucose and plasma TG increases. Mice consuming coffee pulp also had lower body fat and liver TG compared to the model group. qPCR results showed that the expression of transcription factors (Srebp1, PPARγ) and genes (Fasn, CideA, Plin3, Plin4, Plin5) related to DNL and lipid droplets (LD) formation in the liver of mice consuming coffee pulp were significantly lower than those of the control group.

Our study demonstrated that coffee pulp can attenuate HFD-induced disorders of glucose and lipid metabolism, and this effect may be related to the key pathways of lipid synthesis DNL and LD formation pathways in the liver.

The protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (SHP-1) plays an important role in modulating glucose and lipid homeostasis. We previously suggested a potential role of SHP-1 in the regulation of peroxisome proliferator-activated receptor γ2 (PPARγ2) expression and activity but the mechanisms were unexplored. PPARγ2 is the master regulator of adipogenesis, but how its activity is regulated by tyrosine phosphorylation is largely unknown. Here, we found that SHP-1 binds to PPARγ2 primarily via its N-terminal SH2-domain. We confirmed the phosphorylation of PPARγ2 on tyrosine-residue 78 (Y78), which was reduced by SHP-1 in vitro resulting in decreased PPARγ2 stability. Loss of SHP-1 led to elevated, agonist-induced expression of the classical PPARγ2 targets FABP4 and CD36, concomitant with increased lipid content in cells expressing PPARγ2, an effect blunted by abrogation of PPARγ2 phosphorylation. Collectively, we discovered that SHP-1 affects the stability of PPARγ2 through dephosphorylation thereby influencing adipogenesis.

The cell death-inducing DFF45-like effector (CIDE) proteins, including Cidea, Cideb, and Cidec/Fsp27, regulate various aspects of lipid homeostasis, including lipid storage, lipolysis, and lipid secretion. This review focuses on the physiological roles of CIDE proteins based on studies on knockout mouse models and human patients bearing CIDE mutations. The primary cellular function of CIDE proteins is to localize to lipid droplets (LDs) and to control LD fusion and growth across different cell types. We propose a four-step process of LD fusion, characterized by (a) the recruitment of CIDE proteins to the LD surface and CIDE movement, (b) the enrichment and condensate formation of CIDE proteins to form LD fusion plates at LD-LD contact sites, (c) lipid transfer through lipid-permeable passageways within the fusion plates, and (d) the completion of LD fusion. Lastly, we outline CIDE-interacting proteins as regulatory factors, as well as their contribution in LD fusion.

Obesity is a significant risk factor for several chronic diseases. However, pre-menopausal females are protected against high-fat diet (HFD)-induced obesity and its adverse effects. The pregnane X receptor (PXR, NR1I2), a xenobiotic-sensing nuclear receptor, promotes short-term obesity-associated liver disease only in male mice but not in females. Therefore, the current study investigated the metabolic and pathophysiological effects of a long-term 52-week HFD in female wild-type (WT) and PXR-KO mice and characterized the PXR-dependent molecular pathways involved. After 52 weeks of HFD ingestion, the body and liver weights and several markers of hepatotoxicity were significantly higher in WT mice than in their PXR-KO counterparts. The HFD-induced liver injury in WT female mice was also associated with upregulation of the hepatic mRNA levels of peroxisome proliferator-activated receptor gamma (Pparg), its target genes, fat-specific protein 27 (Fsp27), and the liver-specific Fsp27b involved in lipid accumulation, apoptosis, and inflammation. Notably, PXR-KO mice displayed elevated hepatic Cyp2a5 (anti-obesity gene), aldo-keto reductase 1b7 (Akr1b7), glutathione-S-transferase M3 (Gstm3) (antioxidant gene), and AMP-activated protein kinase (AMPK) levels, contributing to protection against long-term HFD-induced obesity and inflammation. RNA sequencing analysis revealed a general blunting of the transcriptomic response to HFD in PXR-KO compared to WT mice. Pathway enrichment analysis demonstrated enrichment by HFD for several pathways, including oxidative stress and redox pathway, cholesterol biosynthesis, and glycolysis/gluconeogenesis in WT but not PXR-KO mice. In conclusion, this study provides new insights into the molecular mechanisms by which PXR deficiency protects against long-term HFD-induced severe obesity and its adverse effects in female mice.

RNA methylation modifications, as a widespread type of modification in eukaryotic cells, especially N6-methyladenosine (m6A), are associated with many activities in organisms, including macrophage polarization and progression of non-alcoholic steatohepatitis (NASH). Macrophages in the liver are of diverse origin and complex phenotype, exhibiting different functions in development of NASH. In the review, we discuss the functions of m6A and m6A-related enzymes in macrophage polarization. Furthermore, we retrospect the role of macrophage polarization in NASH. Finally, we discuss the prospects of m6A in macrophages and NASH, and provide guidance for the treatment of NASH.

Lipid droplets are the essential organelle for storing lipids in a cell. Within the variety of the human body, different cells store, utilize and release lipids in different ways, depending on their intrinsic function. However, these differences are not well characterized and, especially in the context of ageing, represent a key factor for cardiometabolic diseases. Whole body lipid homeostasis is a central interest in the field of cardiometabolic diseases. In this review we characterize lipid droplets and their utilization via autophagy and describe their diverse fate in three cells types central in cardiometabolic dysfunctions: adipocytes, hepatocytes, and macrophages.

Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the role of liver-specific CPT1a on hepatic lipid metabolism.

Male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (60% kcal fat) for 15 weeks. Mice were necropsied after a 16 h fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging, kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis (Plin2, Cidec, G0S2) and in polyunsaturated fatty acid metabolism (Elovl5, Fads1, Elovl2), while only female LKO mice increased genes involved in inflammation (Ly6d, Mmp12, Cxcl2). Kinase profiling showed decreased protein kinase A activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice.

Liver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury.

The pathophysiology of non-alcoholic steatohepatitis (NASH) encompasses a complex set of intra- and extrahepatic driving mechanisms, involving numerous metabolic, inflammatory, vascular and fibrogenic pathways. The peroxisome proliferator-activated receptors (PPARs) α, β/δ and γ belong to the nuclear receptor family of ligand-activated transcription factors. Activated PPARs modulate target tissue transcriptomic profiles, enabling the body's adaptation to changing nutritional, metabolic and inflammatory environments. PPARs hence regulate several pathways involved in NASH pathogenesis. Whereas single PPAR agonists exert robust anti-NASH activity in several preclinical models, their clinical effects on histological endpoints of NASH resolution and fibrosis regression appear more modest. Simultaneous activation of several PPAR isotypes across different organs and within-organ cell types, resulting in pleiotropic actions, enhances the therapeutic potential of PPAR agonists as pharmacological agents for NASH and NASH-related hepatic and extrahepatic morbidity, with some compounds having already shown clinical efficacy on histological endpoints.

Tissues within an organism and even cell types within a tissue can age with different velocities. However, it is unclear whether cells of one type experience different aging trajectories within a tissue depending on their spatial location. Here, we used spatial transcriptomics in combination with single-cell ATAC-seq and RNA-seq, lipidomics and functional assays to address how cells in the male murine liver are affected by age-related changes in the microenvironment. Integration of the datasets revealed zonation-specific and age-related changes in metabolic states, the epigenome and transcriptome. The epigenome changed in a zonation-dependent manner and functionally, periportal hepatocytes were characterized by decreased mitochondrial fitness, whereas pericentral hepatocytes accumulated large lipid droplets. Together, we provide evidence that changing microenvironments within a tissue exert strong influences on their resident cells that can shape epigenetic, metabolic and phenotypic outputs.

Recent findings elucidated hepatic PPARγ functions as a steatogenic-inducer gene that activates de novo lipogenesis, and is involved in regulation of glucose homeostasis, lipid accumulation, and inflammation response. This study delved into a comprehensive analysis of how PPARγ signaling affects the exercise-induced improvement of insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD), along with its underlying mechanism.

Chronic and acute swimming exercise intervention were conducted in each group mice. IR status was assessed by GTT and ITT assays. Serum inflammatory cytokines were detected by Elisa assays. PPARγ and its target genes expression were detected by qPCR assay. Relative protein levels were quantified via Western blotting. ChIP-qPCR assays were used to detect the enrichment of PPARγ on its target genes promoter.

Through an exploration of a high-fat diet (HFD)-induced IR and NAFLD model, both chronic and acute swimming exercise training led to significant reductions in body weight and visceral fat mass, as well as hepatic lipid accumulation. The exercise interventions also demonstrated a significant amelioration in IR and the inflammatory response. Meanwhile, swimming exercise significantly inhibited PPARγ and its target genes expression induced by HFD, containing CD36, SCD1 and PLIN2. Furthermore, swimming exercise presented significant modulation on regulatory factors of PPARγ expression and transcriptional activity.

The findings suggest that swimming exercise can improve lipid metabolism in IR and NAFLD, possibly through PPARγ signaling in the liver of mice.

To study the characteristics of genes and metabolites related to intramuscular fat (IMF) content with less influence by breed background and individual differences, the skeletal muscle samples from 40 Beijing black pigs with either high or low IMF content were used to perform transcriptome and metabolome analyses. About 99 genes (twofold-change) were differentially expressed. Up-regulated genes in the high IMF pigs were mainly related to fat metabolism. The key genes in charge of IMF deposition are ADIPOQ, CIDEC, CYP4B1, DGAT2, LEP, OPRL1, PLIN1, SCD, and THRSP. KLHL40, TRAFD1, and HSPA6 were novel candidate genes for the IMF trait due to their high abundances. In the low IMF pigs, the differentially expressed genes involved in virus resistance were up-regulated. About 16 and 18 differential metabolites (1.5 fold-change) were obtained in the positive and negative modes, respectively. Pigs with low IMF had weaker fatty acid oxidation due to the down-regulation of various carnitines. Differentially expressed genes were more important in determining IMF deposition than differential metabolites because relatively few differential metabolites were obtained, and they were merely the products under the physiological status of diverged IMF content. This study provided valuable information for further studies on IMF deposition.

Xenobiotics are primarily metabolized by hepatocytes in the liver, and primary human hepatocytes are the gold standard model for the assessment of drug efficacy, safety, and toxicity in the early phases of drug development. Recent advances in single-cell genomics demonstrate liver zonation and ploidy as main drivers of cellular heterogeneity. However, little is known about the impact of hepatocyte specialization on liver function upon metabolic challenge, including hepatic metabolism, detoxification, and protein synthesis.

Here, we investigate the metabolic capacity of individual human hepatocytes in vitro. We assess how chronic accumulation of lipids enhances cellular heterogeneity and impairs the metabolisms of drugs. Using a phenotyping five-probe cocktail, we identify four functional subgroups of hepatocytes responding differently to drug challenge and fatty acid accumulation. These four subgroups display differential gene expression profiles upon cocktail treatment and xenobiotic metabolism-related specialization. Notably, intracellular fat accumulation leads to increased transcriptional variability and diminishes the drug-related metabolic capacity of hepatocytes.

Our results demonstrate that, upon a metabolic challenge such as exposure to drugs or intracellular fat accumulation, hepatocyte subgroups display different and heterogeneous transcriptional responses.

Sphingomyelin synthase (SMS)-related protein (SMSr) is a phosphatidylethanolamine phospholipase C (PE-PLC) that is conserved and ubiquitous in mammals. However, its biological function is still not clear. We previously observed that SMS1 deficiency-mediated glucosylceramide accumulation caused nonalcoholic fatty liver diseases (NAFLD), including nonalcoholic steatohepatitis (NASH) and liver fibrosis. Here, first, we evaluated high-fat diet/fructose-induced NAFLD in Smsr KO and WT mice. Second, we evaluated whether SMSr deficiency can reverse SMS1 deficiency-mediated NAFLD, using Sms1/Sms2 double and Sms1/Sms2/Smsr triple KO mice. We found that SMSr/PE-PLC deficiency attenuated high-fat diet/fructose-induced fatty liver and NASH, and attenuated glucosylceramide accumulation-induced NASH, fibrosis, and tumor formation. Further, we found that SMSr/PE-PLC deficiency reduced the expression of many inflammatory cytokines and fibrosis-related factors, and PE supplementation in vitro or in vivo mimicked the condition of SMSr/PE-PLC deficiency. Furthermore, we demonstrated that SMSr/PE-PLC deficiency or PE supplementation effectively prevented membrane-bound β-catenin transfer to the nucleus, thereby preventing tumor-related gene expression. Finally, we observed that patients with NASH had higher SMSr protein levels in the liver, lower plasma PE levels, and lower plasma PE/phosphatidylcholine ratios, and that human plasma PE levels are negatively associated with tumor necrosis factor-α and transforming growth factor β1 levels. In conclusion, SMSr/PE-PLC deficiency causes PE accumulation, which can attenuate fatty liver, NASH, and fibrosis. These results suggest that SMSr/PE-PLC inhibition therapy may mitigate NAFLD.

Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the impact by which liver-specific CPT1a deletion impacts hepatic lipid metabolism.

Six-to-eight-week old male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (HFD; 60% kcal fat) for 15 weeks. Mice were necropsied after a 16 hour fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase (ALT) levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in both whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis ( Plin2 , Cidec , G0S2 ) and in polyunsaturated fatty acid (PUFA) metabolism ( Elovl5, Fads1, Elovl2 ), while only female LKO mice increased genes involved in inflammation ( Ly6d, Mmp12, Cxcl2 ). Kinase profiling showed decreased protein kinase A (PKA) activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice.

Liver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury.

The nuclear receptors peroxisome proliferator-activated receptor gamma (PPARγ) and adipogenin (ADIG) play vital roles in lipid metabolism. However, the interaction between PPARγ and ADIG during liver steatosis remains unclear. In this study, we aimed to investigate the role of PPARγ in the transcriptional regulation of hepatic ADIG expression. Adig was found to be highly expressed in various fatty liver mouse models. Although hepatic Adig was expressed at high levels in the fatty liver of type 2 diabetic ob/ob mice and was upregulated by PPARγ agonist treatment, it was expressed at significantly low levels in liver-specific Pparg-knockout mice. Moreover, hepatic Adig expression was observed in other mouse models of liver steatosis, such as the leptin receptor mutant db/db and alcohol-fed mice. Adig was also highly expressed in the white and brown adipose tissues, skeletal muscles, and heart of ob/ob mice. Reporter and electromobility shift assays showed that PPARγ positively regulates Adig transcriptional activity by directly binding to a functional PPARγ-responsive element in the promoter region. Our results indicate that Adig is a novel target gene of hepatic PPARγ in liver steatosis.

Alcohol-associated liver disease (ALD) represents a spectrum of alcohol use-related liver diseases. Outside of alcohol abstinence, there are currently no Food and Drug Administration-approved treatments for advanced ALD, necessitating a greater understanding of ALD pathogenesis and potential molecular targets for therapeutic intervention. The ABL-family proteins, including ABL1 and ABL2, are non-receptor tyrosine kinases that participate in a diverse set of cellular functions. We investigated the role of the ABL kinases in alcohol-associated liver disease.

We used samples from patients with ALD compared with healthy controls to elucidate a clinical phenotype. We established strains of liver-specific Abl1 and Abl2 knockout mice and subjected them to the National Institute on Alcohol Abuse and Alcoholism acute-on-chronic alcohol feeding regimen. Murine samples were subjected to RNA sequencing, AST, Oil Red O staining, H&E staining, Western blotting, and quantitative polymerase chain reaction to assess phenotypic changes after alcohol feeding. In vitro modeling in HepG2 cells as well as primary hepatocytes from C57BL6/J mice was used to establish this mechanistic link of ALD pathogenesis.

We demonstrate that the ABL kinases are highly activated in ALD patient liver samples as well as in liver tissues from mice subjected to an alcohol feeding regimen. We found that the liver-specific knockout of Abl2, but not Abl1, attenuated alcohol-induced steatosis, liver injury, and inflammation. Subsequent RNA sequencing and gene set enrichment analyses of mouse liver tissues revealed that relative to wild-type alcohol-fed mice, Abl2 knockout alcohol-fed mice exhibited numerous pathway changes, including significantly decreased peroxisome proliferator activated receptor (PPAR) signaling. Further examination revealed that PPARγ, a previously identified regulator of ALD pathogenesis, was induced upon alcohol feeding in wild-type mice, but not in Abl2 knockout mice. In vitro analyses revealed that shRNA-mediated knockdown of ABL2 abolished the alcohol-induced accumulation of PPARγ as well as subsequent lipid accumulation. Conversely, forced overexpression of ABL2 resulted in increased PPARγ protein expression. Furthermore, we demonstrated that the regulation of hypoxia inducible factor 1 subunit alpha (HIF1α) by ABL2 is required for alcohol-induced PPARγ expression. Furthermore, treatment with ABL kinase inhibitors attenuated alcohol-induced PPARγ expression, lipid droplet formation, and liver injury.

On the basis of our current evidence, we propose that alcohol-induced ABL2 activation promotes ALD through increasing HIF1α and the subsequent PPARγ expression, and ABL2 inhibition may serve as a promising target for the treatment of ALD.

Mammalian lipid droplets (LDs) are specialized cytosolic organelles consisting of a neutral lipid core surrounded by a membrane made up of a phospholipid monolayer and a specific population of proteins that varies according to the location and function of each LD. Over the past decade, there have been significant advances in the understanding of LD biogenesis and functions. LDs are now recognized as dynamic organelles that participate in many aspects of cellular homeostasis plus other vital functions. LD biogenesis is a complex, highly-regulated process with assembly occurring on the endoplasmic reticulum although aspects of the underpinning molecular mechanisms remain elusive. For example, it is unclear how many enzymes participate in the biosynthesis of the neutral lipid components of LDs and how this process is coordinated in response to different metabolic cues to promote or suppress LD formation and turnover. In addition to enzymes involved in the biosynthesis of neutral lipids, various scaffolding proteins play roles in coordinating LD formation. Despite their lack of ultrastructural diversity, LDs in different mammalian cell types are involved in a wide range of biological functions. These include roles in membrane homeostasis, regulation of hypoxia, neoplastic inflammatory responses, cellular oxidative status, lipid peroxidation, and protection against potentially toxic intracellular fatty acids and lipophilic xenobiotics. Herein, the roles of mammalian LDs and their associated proteins are reviewed with a particular focus on their roles in pathological, immunological and anti-toxicological processes.

Chronic liver disease (CLD) has emerged as a leading cause of human deaths. It caused 1.32 million deaths in 2017, which affected men more than women by a two-to-one ratio. There are various causes of CLD, including obesity, excessive alcohol consumption, and viral infection. Among them, non-alcoholic fatty liver disease (NAFLD), one of obesity-induced liver diseases, is the major cause, representing the cause of more than 50% of cases. Fucoxanthin, a carotenoid mainly found in brown seaweed, exhibits various biological activities against NAFLD. Its role in NAFLD appears in several mechanisms, such as inducing thermogenesis in mitochondrial homeostasis, altering lipid metabolism, and promoting anti-inflammatory and anti-oxidant activities. The corresponding altered signaling pathways are the β3-adorenarine receptor (β3Ad), proliferator-activated receptor gamma coactivator (PGC-1), adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor (PPAR), sterol regulatory element binding protein (SREBP), nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), protein kinase B (AKT), SMAD2/3, and P13K/Akt pathways. Fucoxanthin also exhibits anti-fibrogenic activity that prevents non-alcoholic steatohepatitis (NASH) development.

Oxysterol-binding protein-like 3 (OSBPL3) plays a key role in the development of fatty liver disease. Herein, we found that OSBPL3 is highly expressed in the fatty liver of humans and mice. Although high expression of Osbpl3 was observed in the fatty liver of type 2 diabetic ob/ob mice, liver-specific Pparg knockout ameliorated this increase in these mice. Moreover, high hepatic Osbpl3 expression was observed in other mice models of fatty liver disease, such as leptin receptor-mutant db/db and alcohol-fed mice. Analysis of the human liver transcriptome data revealed that hepatic OSBPL3 expression is higher in patients with advanced non-alcoholic fatty liver disease (NAFLD) when compared to those with mild NAFLD. Reporter and electrophoretic mobility shift assays showed that PPARγ positively regulates Osbpl3 transcription by binding to the two functional PPARγ-responsive elements present in the 5' upstream region. Overall, our results indicate that Osbpl3 is a novel PPARγ target in the fatty liver.

Dysregulated lipid droplet accumulation has been identified as one of the main contributors to liver steatosis during nonalcoholic fatty liver disease (NAFLD). However, the underlying molecular mechanisms for excessive lipid droplet formation in the liver remain largely unknown. In the current study, hepatic E4 promoter-binding protein 4 (E4BP4) plays a critical role in promoting lipid droplet formation and liver steatosis in a high-fat diet (HFD)-induced NAFLD mouse model. Hepatic E4bp4 deficiency (E4bp4-LKO) protects mice from HFD-induced liver steatosis independently of obesity and insulin resistance. Our microarray study showed a markedly reduced expression of lipid droplet binding genes, such as Fsp27, in the liver of E4bp4-LKO mice. E4BP4 is both necessary and sufficient to activate Fsp27 expression and lipid droplet formation in primary mouse hepatocytes. Overexpression of Fsp27 increased lipid droplets and triglycerides in E4bp4-LKO primary mouse hepatocytes and restored hepatic steatosis in HFD-fed E4bp4-LKO mice. Mechanistically, E4BP4 enhances the transactivation of Fsp27 by CREBH in hepatocytes. Furthermore, E4BP4 is modified by SUMOylation, and HFD feeding induces deSUMOylation of hepatic E4BP4. SUMOylation of five lysine residues of E4BP4 is critical for the downregulation of Fsp27 and lipid droplets by cAMP signaling in hepatocytes. Taken together, this study revealed that E4BP4 drives liver steatosis in HFD-fed mice through its regulation of lipid droplet binding proteins. Our study also highlights the critical role of deSUMOylation of hepatic E4BP4 in promoting NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is becoming a leading cause of chronic liver disease worldwide. The molecular events that influence disease progression from non-alcoholic fatty liver (NAFL) to aggressive non-alcoholic steatohepatitis (NASH) remain incompletely understood, leading to lack of mechanism-based targeted treatment options for NASH. This study aims to identify early signatures associated with disease progression from NAFL to NASH in mice and humans.

Male C57BL/6J mice were fed a high-fat, -cholesterol, and - fructose (HFCF) diet for up to 9 months. The extent of steatosis, inflammation, and fibrosis was evaluated in liver tissues. Total RNA sequencing (RNA-seq) was conducted to determine liver transcriptomic changes.

After being fed the HFCF diet, mice sequentially developed steatosis, early steatohepatitis, steatohepatitis with fibrosis, and eventually spontaneous liver tumor. Hepatic RNA-seq revealed that the key signatures during steatosis progression to early steatohepatitis were pathways related to extracellular matrix organization and immune responses such as T cell migration, arginine biosynthesis, C-type lectin receptor signaling, and cytokine-cytokine receptor interaction. Genes regulated by transcription factors forkhead box M1 (FOXM1) and negative elongation factor complex member E (NELFE) were significantly altered during disease progression. This phenomenon was also observed in patients with NASH.

In summary, we identified early signatures associated with disease progression from NAFL to early NASH in a mouse model that recapitulated key metabolic, histologic, and transcriptomic changes seen in humans. The findings from our study may shed light on the development of novel preventative, diagnostic, and therapeutic strategies for NASH.

Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ's ability to activate target genes in a cellular context is currently poorly understood. Here we take advantage of two previously uncharacterized lipodystrophy mutations, R212Q and E379K, that are predicted to interfere with the interaction of the hinge of PPARγ with DNA and with the interaction of PPARγ ligand binding domain (LBD) with the DNA-binding domain (DBD) of the retinoid X receptor, respectively. Using biochemical and genome-wide approaches we show that these mutations impair PPARγ function on an overlapping subset of target enhancers. The hinge region-DNA interaction appears mostly important for binding and remodelling of target enhancers in inaccessible chromatin, whereas the PPARγ-LBD:RXR-DBD interface stabilizes the PPARγ:RXR:DNA ternary complex. Our data demonstrate how in-depth analyses of lipodystrophy mutants can unravel molecular mechanisms of PPARγ function.

Dennd5b plays a pivotal role in intestinal absorption of dietary lipids in mice and is associated with body mass index in humans. This study examined the impact of whole-body Dennd5b deletion on plasma lipid concentrations, atherosclerosis, and hepatic lipid metabolism in mice. Hypercholesterolemia was induced in Dennd5b^-/- mice by infection with an adeno-associated virus expressing the proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) gain-of-function mutation (PCSK9D377Y) and feeding a Western diet for 12 weeks. Body weight and plasma lipid concentrations were monitored over 12 weeks, and then aortic atherosclerosis and hepatic lipid content were quantified. Compared to Dennd5b^+/+ mice, Dennd5b^-/- mice were resistant to diet-induced weight gain and PCSK9-induced hypercholesterolemia. Atherosclerosis quantified by en face analysis and in aortic root sections, revealed significantly smaller lesions in Dennd5b^-/- compared to Dennd5b^+/+ mice. Additionally, Dennd5b^-/- mice had significantly less hepatic lipid content (triglyceride and cholesterol) compared to Dennd5b^+/+ mice. To gain insight into the basis for reduced hepatic lipids, quantitative PCR was used to measure mRNA abundance of genes involved in hepatic lipid metabolism. Key genes involved in hepatic lipid metabolism and lipid storage were differentially expressed in Dennd5b^-/- liver including Pparg, Cd36, and Pnpla3. These findings demonstrate a significant impact of Dennd5b on plasma and hepatic lipid concentrations and resistance to PCSK9-induced hypercholesterolemia in the absence of Dennd5b.

Ban-xia-xie-xin-tang (BXXXT) has been applied in treating metabolic diseases, such as nonalcohol fatty liver disease, diabetes mellitus, and obesity. However, the underlying molecular mechanism of BXXXT in treating diabetes mellitus is unknown.

To clarify the underlying molecular mechanism of BXXXT in alleviating hepatic steatosis in high-fat diet (HFD)-fed mice.

After 12 weeks of HFD treatment, mice were administered BXXXT for 4 weeks. The main chemical components of BXXXT were identified by UPLC-TQ-MS/MS. Indicators associated with insulin resistance and lipid metabolism were detected. The effect of improving glucose and lipid metabolism between BXXXT and the different components was compared. Differentially expressed genes (DEGs) were identified by hepatic transcriptomics. Key DEGs and proteins were further detected by real-time quantitative polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence staining. LDs and mitochondria were detected by transmission electron microscopy.

First of all, our data demonstrated that the capacity to improve glucose and lipid metabolism for BXXXT was significantly superior to different components of BXXXT. BXXXT was found to improve HFD-induced insulin resistance. Moreover, BXXXT decreased weight, serum/hepatic triglycerides, total cholesterol, and FFAs to alleviate HFD-induced hepatic steatosis. According to the results of the hepatic transcription, Cidea and Cidec were identified as critical DEGs for promoting LD fusion and reducing FFAs β-oxidation in mitochondria and peroxisome resulting in hepatic steatosis, which was reversed by BXXXT.

BXXXT ameliorates HFD-induced hepatic steatosis and insulin resistance by increasing Cidea and Cidec-mediated mitochondrial and peroxisomal fatty acid oxidation, which may provide a potential strategy for therapy of NAFLD and T2DM.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and affects about 25% of the population globally. Obesity and diabetes are the main causes of the disease characterized by excessive accumulation of lipids in the liver. There is currently no direct pharmacological treatments for NAFLD. Dietary intervention and lifestyle modification are the key strategies in the prevention and treatment of the disease. Soy consumption is associated with many health benefits such as decreased incidence of coronary heart disease, type-2 diabetes, atherosclerosis and obesity. The hypolipidemic functions of soy components have been shown in both animal studies and human clinical trials. Dietary soy proteins and associated isoflavones suppressed the formation and accumulation of lipid droplets in the liver and improved NAFLD-associated metabolic syndrome. The molecular mechanism(s) underlying the effects of soy components are mainly through modulation of transcription factors, sterol regulatory element-binding protein-1 and peroxisome proliferator-activated receptor-γ2, and expressions of their target genes involved in lipogenesis and lipolysis as well as lipid droplet-promoting protein, fat-specific protein-27. Inclusion of appropriate amounts of soy protein and isoflavones in the diets might be a useful approach to decrease the prevalence of NAFLD and mitigate disease burden.

Sterol O-acyltransferase 2 (Soat2) encodes acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2), which synthesizes cholesteryl esters in hepatocytes and enterocytes fated either to storage or to secretion into nascent triglyceride-rich lipoproteins.

We aimed to unravel the molecular mechanisms leading to reduced hepatic steatosis when Soat2 is depleted in mice.

Soat2-/- and wild-type mice were fed a high-fat, a high-carbohydrate, or a chow diet, and parameters of lipid and glucose metabolism were assessed.

Glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), oral glucose tolerance (OGTT), and insulin tolerance tests significantly improved in Soat2-/- mice, irrespective of the dietary regimes (2-way ANOVA). The significant positive correlations between area under the curve (AUC) OGTT (r = 0.66, p < 0.05), serum fasting insulin (r = 0.86, p < 0.05), HOMA-IR (r = 0.86, p < 0.05), Adipo-IR (0.87, p < 0.05), hepatic triglycerides (TGs) (r = 0.89, p < 0.05), very-low-density lipoprotein (VLDL)-TG (r = 0.87, p < 0.05) and the hepatic cholesteryl esters in wild-type mice disappeared in Soat2-/- mice. Genetic depletion of Soat2 also increased whole-body oxidation by 30% (p < 0.05) compared to wild-type mice.

Our data demonstrate that ACAT2-generated cholesteryl esters negatively affect the metabolic control by retaining TG in the liver and that genetic inhibition of Soat2 improves liver steatosis via partitioning of lipids into secretory (VLDL-TG) and oxidative (fatty acids) pathways.