Jul 2026· Journal of Dairy Science· 0 citations· 39 references
Medicine
TL;DR
Protein palmitoylation is established as both a critical pathological mechanism and a promising therapeutic target for fatty liver in dairy cows.
Abstract
Elevated circulating nonesterified fatty acids (NEFA) represent a key pathological feature in dairy cows with fatty liver. Palmitic acid (PA), a major component of NEFA, can be enzymatically attached to proteins via a reversible post-translational modification known as palmitoylation, which potently modulates protein activity and function. Studies have revealed that aberrant hepatic palmitoylation is a crucial mechanism promoting lipid accumulation in non-ruminants. Nevertheless, the extent and pathological relevance of hepatic protein palmitoylation in dairy cows with fatty liver have largely remained unexplored. Therefore, this study was conducted to determine the status of hepatic protein palmitoylation in dairy cows with fatty liver and to elucidate its functional role in the development of hepatic steatosis. Blood and liver samples were collected from 10 dairy cows with fatty liver (hepatic triglyceride [TG] content >5%) and 10 control cows (hepatic TG content <1%) that had a similar number of lactations (median: 3, range: 2 to 4) and days in milk (median: 9 d, range: 5 to 14 d). To determine the effects of NEFA on palmitoylation, hepatocytes isolated from calves were treated with 1.2 mM NEFA for 12 h. To investigate the effects of palmitoylation on lipid accumulation in bovine hepatocytes, the cells were treated with 1.2 mM NEFA for 12 h in the presence or absence of a palmitoylation inhibitor (2-bromohexadecanoic acid). The results revealed that dairy cows with fatty liver exhibited liver injury and elevated hepatic palmitoyl-CoA content. Moreover, fatty liver dairy cows showed higher hepatic mRNA abundance of ZDHHC4/5/14/20 and lower mRNA abundance of ZDHHC3/19/21/23/24. In contrast, the mRNA abundance of depalmitoylase-related genes, including lysophospholipase 1 (LYPLA1 and LYPLA2), palmitoyl-protein thioesterase 1 (PPT1 and PPT2) and abhydrolase domain containing 17 (ABHD17A, ABHD17B and ABHD17C), was lower in the liver of cows with fatty liver than in control cows. Consistently, a greater abundance of palmitoylated proteins was observed in the liver of dairy cows with fatty liver. In vitro, NEFA treatment induced lipid accumulation, cell injury, and aberrant protein palmitoylation in bovine hepatocytes. Additionally, the upregulation of palmitoyltransferases and downregulation of depalmitoylases observed in cows with fatty liver were recapitulated in NEFA-treated bovine hepatocytes. Importantly, pharmacological inhibition of palmitoylation significantly alleviated NEFA-induced lipid accumulation and cell damage in bovine hepatocytes. Overall, these findings establish protein palmitoylation as both a critical pathological mechanism and a promising therapeutic target for fatty liver in dairy cows.
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally. Chenodeoxycholic acid (CDCA), a key component of bile acids, improves hepatic lipid metabolism. The present study aimed to investigate whether CDCA regulates hepatic lipid metabolism by interacting with pyruvate kinase (PK), and to elucidate the underlying molecular mechanism. High-fat cell and murine models were generated. The levels of total cholesterol (TC), triglycerides (TG), superoxide dismutase (SOD) and malondialdehyde (MDA) in cells and animal livers were measured. BODIPY and Oil Red staining were employed to detect the lipid droplet content. Reverse transcription-quantitative PCR was used to assess the expression of the lipid-related genes. Immunoprecipitation and molecular docking were used to examine the interaction between CDCA and PK, as well as their interaction sites. The effects of their binding on PK activity and pyruvate synthesis were investigated. Both in vitro and in vivo experiments demonstrated that compared with the high-fat group, the TG, TC and MDA levels in the CDCA-treated group were markedly reduced. In addition, lipid droplet count was markedly decreased and SOD activity was increased. The mRNA expression levels of lipid synthesis genes (such as fatty acid synthase and sterol regulatory element-binding transcription factor 1) were notably decreased, whereas those of lipid metabolism genes (CTP synthase 1 and peroxisome proliferator-activated receptor α) exhibited the opposite trend. CDCA specifically bound to the PK-M2 subtype, which promoted PK activity and pyruvate production. Pretreatment with a PK inhibitor completely reversed lipid synthesis inhibition and β-oxidation enhancement induced by CDCA. CDCA notably ameliorated hepatic lipid deposition, and its underlying mechanism was revealed to be closely associated with the direct binding of CDCA to PK and subsequent enhancement of PK activity.
BACKGROUND & AIMS
Obesity is a major driver of metabolic dysfunction-associated steatotic liver disease (MASLD), yet the molecular mechanisms linking excess adiposity to hepatocellular lipid accumulation remain incompletely defined. We investigated whether circulating fatty acid-binding protein 4 (FABP4) mediates adipocyte-hepatocyte lipid crosstalk in obesity.
METHODS
FABP4 expression and localization were analyzed in human liver specimens (n=55) and multiple mouse models of hepatic steatosis. Whole-body and tissue-specific Fabp4 knockout mice (n=7-10/group) were subjected to high-fat diet feeding and assessed for hepatic steatosis. Hepatocyte fatty acid uptake assays were performed in vitro. A high affinity humanized monoclonal antibody targeting FABP4 was generated and evaluated for its effects on hepatocyte binding, lipid uptake, and hepatic steatosis in obese mouse models.
RESULTS
FABP4 protein, but not mRNA, was markedly increased in hepatocytes from steatotic human livers (p<0.05) and obese mice (p<0.0001), suggesting an extrinsic source. Adipocyte-specific deletion of Fabp4 protected mice from diet-induced hepatic steatosis without affecting body weight or circulating lipid levels (p<0.01). Mechanistically, circulating FABP4 directly bound to hepatocytes and facilitated free fatty acid uptake. Neutralization of circulating FABP4 with a humanized monoclonal antibody blocked hepatocyte binding (p<0.001), reduced fatty acid uptake (p<0.01), and significantly attenuated hepatic steatosis across multiple obese mouse models.
CONCLUSIONS
These findings identify circulating FABP4 as a pathogenic lipid chaperone that links adipose tissue dysfunction to hepatocellular lipid accumulation. Targeting circulating FABP4 represents a promising strategy for prevention and treatment of obesity-associated hepatic steatosis.
IMPACT AND IMPLICATIONS
This study identifies circulating FABP4 as an endocrine lipid chaperone that mediates pathogenic adipose-liver crosstalk in obesity by directly promoting hepatocellular fatty acid uptake. The accumulation of FABP4 protein in hepatocytes in the absence of transcriptional induction reveals a previously unrecognized mechanism driving hepatic steatosis independently of systemic lipid levels. Importantly, neutralization of circulating FABP4 markedly attenuates steatosis in obese mouse models, establishing FABP4 as a tractable therapeutic target and supporting adipose-derived lipid carriers as a new intervention axis for MASLD.
Xingshan Jiang, Anthony Avellino, Jianyu Yu et al.· JHEP Reports· 0 citations
Metabolic dysfunction-associated steatotic liver disease (MASLD) primarily results from excessive nutrient consumption, with lifestyle modifications, particularly dietary interventions, constituting a principal strategy for its management. This study sought to examine the ameliorative effects of a quinoa diet (QD) on hepatic lipid metabolism in mice with MASLD. Six-week-old male C57BL/6J mice were fed with a QD for 12 weeks, and age-matched male mice were subjected to a high-fat diet (HFD) to establish obese MASLD models, followed by QD intervention. Compared with the chow diet (CD) group, QD supplementation maintained lower levels of Lee's index, serum AST and ALT, confirming its regulatory effect on hepatic fat accumulation. In MASLD mice, QD supplementation markedly decreased Lee's index, blood glucose, ALT, AST, LDL-C, TC and TG contents. It also downregulated the gene expression of ACC, FAS and SCD-1 as well as the protein levels of PPARγ and PLIN2, thereby alleviating HFD-triggered hepatic lipid metabolism disorders. Lipids and lipid-like molecules were the most significantly altered metabolites in QD-treated mice, accounting for 50.87% of all differential metabolites. Collectively, quinoa demonstrates the capacity to enhance hepatic lipid metabolism in mice with metabolic-associated steatotic liver disease (MASLD), with the PPARγ-PLIN2 signaling pathway potentially serving as a central therapeutic target. These findings indicate that quinoa holds significant promise as a functional food for the intervention and mitigation of MASLD.
Introduction Urea shows substantial potential as a cost-effective alternative to soybean meal in ruminant production. Given the critical role of subcutaneous adipose tissue (SAT) in meat quality, this study evaluated the effects of different dietary urea levels on the histomorphology, fatty acid composition, lipidomic profiles, and volatile flavour compounds of SAT in Tibetan sheep. Methods Eighty female lambs (16.2 ± 1.01 kg, 2 months old) were randomly assigned to four dietary treatments supplemented with 0% (U0), 0.80% (U1), 1.19% (U2), and 1.61% (U3) urea. The 105-day trial comprised a 15-day adaptation period followed by a 90-day experimental period. Results The results indicated that: high urea levels (U2 and U3) disrupted adipocyte integrity, resulting in disordered arrangement, cellular rupture, and a significant reduction in adipocyte diameter (p < 0.05). Increasing dietary urea levels significantly decreased the concentrations of trans monounsaturated fatty acids (e.g., C16:1 T) and n-3 polyunsaturated fatty acids (p < 0.05), while increasing the level of cis monounsaturated fatty acid C18:1n9c (p < 0.05). Lipidomic analysis identified 48 differential lipid molecules (|log2Fold change| ≥ 2, adjusted p < 0.05), primar ily comprising glycerolipids (Triglycerides, Triglycerides) and glycerophospho lipids (phosphatidylcholine, phosphatidylethanolamine, Phosphatidylglycerol). Urea supplementation significantly influenced the volatile compounds profile (p < 0.05); excessive urea (U3) led to ammonia accumulation and pungent off odors, whereas moderate supplementation imparted desirable milky and vanilla aromas. Discussion In conclusion, dietary urea levels affected lipid metabolism and reduced trans-fatty acid content; excessive dietary urea disrupted cell structure, increased ammonia accumulation and reduced aroma-contributing substances in the SAT of Tibetan sheep.
Rongfu Song, Juyuan He, Anum Ali Ahmad et al.· Frontiers in Veterinary Scie...· 0 citations
Consumption of a high-fat diet (HFD) diet is a factor associated with several diseases including obesity and its associated complications, especially liver and kidney dysfunction via promoting derangement of lipid metabolism. It has been reported that fructooligosaccharides (FOS) improve insulin sensitivity and ectopic lipid accumulation. The aim of this study was to investigate the effects of FOS on insulin resistance, liver and renal lipid accumulation, inflammasome formation, oxidative stress and intestinal barrier integrity in an obese rat model. Male Wistar rats were fed a normal (ND) or HFD for 16 weeks. The rats given a HFD were then given FOS at 1 or 2 g/day and metformin at 30 mg/kg/day daily for 8 weeks by oral gavage. The results demonstrated that FOS and metformin improved insulin resistance. FOS showed greater efficacy than metformin in attenuating intestinal barrier leakage. FOS and metformin decreased liver lipid synthesis as evidenced by the downregulation of SREBP1c, FAS and perilipin2. Renal lipid accumulation was restored concomitant with the reduction in renal lipid content and lipotoxicity. Liver and renal inflammation and organ injury were restored to within normal limits. However, FOS had no effect on the antioxidant enzymes via KEAP1/NRF2. Metformin attenuated renal oxidative stress via the suppression of PKCα and the FOXO1 signaling pathway. These suggest that FOS and metformin have the potential to improve gut health and prevent liver and renal complications and could be used as a useful supplement in the obese condition.
Nattavadee Pengrattanachot, Onanong Jaruan, Sasivimon Promsan et al.· Biochimica et Biophysica Act...· 0 citations
The escalating prevalence of obesity necessitates a deeper molecular understanding of how high-fat diets disrupt lipid metabolism. This study aimed to elucidate the potential mechanisms by which dietary fatty acids (FAs) modulate the key lipolytic enzymes, lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL). An integrated in vivo and in silico approach was employed: Wistar rats were fed a standard or hypercaloric cafeteria diet for 8 weeks, after which physiological parameters, tissue lipid content, and enzyme activities were assessed. Molecular docking was used to characterize interactions between diet-specific FAs and enzyme crystal structures. The cafeteria diet induced significant obesity (+32.8% body weight, p < 0.001), adipose expansion (+137%, p < 0.001), pro-atherogenic dyslipidemia (+50.5% plasma triglycerides, p < 0.001), and hepatic steatosis (+56% triglycerides, p < 0.001). Paradoxically, both LPL and HSL activities were significantly upregulated in adipose tissue (+28.6%, p < 0.01 and + 89.7%, p < 0.001, respectively). Docking simulations suggested a potential mechanistic segregation: saturated FAs from the cafeteria diet were predicted to bind a putative allosteric site on LPL chain B, while polyunsaturated FAs from standard chow preferentially docked to the canonical active site on chain A. For HSL, all dietary FAs were predicted to bind with high affinity to an exosite on chain A, distinct from the inhibitor site. Together, these findings propose that dietary FAs may act as allosteric and exosite modulators of lipolytic enzymes, providing a candidate molecular link between diet composition and lipid dysregulation in obesity. This repositioning of dietary lipids as potential regulatory molecules opens new avenues for precision nutrition. However, given the multifaceted compositional differences between the cafeteria and control diets, the observed in vivo effects cannot be attributed solely to saturated versus polyunsaturated fatty acid differences, and these findings require further validation using purified diets and targeted structural approaches.
M. Bensalah, S. Bouanane, F. B. Baba Ahmed· Biochemical and Biophysical...· 0 citations
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