Hepatocellular RECK as a Critical Regulator of Metabolic Dysfunction-associated Steatohepatitis Development.

BACKGROUND & AIMS: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is an extracellular matrix regulator with anti-fibrotic effects. However, its expression and role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis are poorly understood. METHODS: We generated a novel transgenic mouse model with RECK overexpression specifically in hepatocytes to investigate its role in Western diet (WD)-induced liver disease. Proteomic analysis and in vitro studies were performed to mechanistically link RECK to hepatic inflammation and fibrosis. RESULTS: Our results show that RECK expression is significantly decreased in liver biopsies from human patients diagnosed with MASH and correlated negatively with severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Similarly, RECK expression is downregulated in WD-induced MASH in wild-type mice. Hepatocyte-specific RECK overexpression significantly reduced hepatic pathology in WD-induced liver injury. Proteomic analysis highlighted changes in extracellular matrix and cell-signaling proteins. In vitro mechanistic studies linked RECK induction to reduced ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) and ADAM17 activity, amphiregulin release, epidermal growth factor receptor activation, and stellate cell activation. CONCLUSION: Our in vivo and mechanistic in vitro studies reveal that RECK is a novel upstream regulator of inflammation and fibrosis in the diseased liver, its induction is hepatoprotective, and thus highlights its potential as a novel therapeutic in MASH.

Relationship between serum ß-hydroxybutyrate and hepatic fatty acid oxidation in individuals with obesity and NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation that can progress to inflammation (nonalcoholic steatohepatitis, NASH), and fibrosis. Serum ß-hydroxybutyrate (ß-HB), a product of the ketogenic pathway, is commonly used as a surrogate marker for hepatic fatty acid oxidation (FAO). However, it remains uncertain whether this relationship holds true in the context of NAFLD in humans. We compared fasting serum ß-HB levels with direct measurement of liver mitochondrial palmitate oxidation in humans stratified based on NAFLD severity (n = 142). Patients were stratified based on NAFLD activity score (NAS): NAS = 0 (no disease), NAS = 1-2 (mild), NAS = 3-4 (moderate), and NAS ≥ 5 (advanced). Moderate and advanced NAFLD is associated with reductions in liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), serum ß-HB, but not 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) mRNA, relative to no disease. Worsening liver mitochondrial complete palmitate oxidation corresponded with lower HMGCS2 mRNA but not total (complete + incomplete) palmitate oxidation. Interestingly, we found that liver HMGCS2 mRNA and serum ß-HB correlated with liver mitochondrial ß-hydroxyacyl-CoA dehydrogenase (ß-HAD) activity and CPT1A mRNA. Also, lower mitochondrial mass and markers of mitochondrial turnover positively correlated with lower HMGCS2 in the liver. These data suggest that liver ketogenesis and FAO occur at comparable rates in individuals with NAFLD. Our findings support the utility of serum ß-HB to serve as a marker of liver injury and hepatic FAO in the context of NAFLD.NEW & NOTEWORTHY Serum ß-hydroxybutyrate (ß-HB) is frequently utilized as a surrogate marker for hepatic fatty acid oxidation; however, few studies have investigated this relationship during states of liver disease. We found that the progression of nonalcoholic fatty liver disease (NAFLD) is associated with reductions in circulating ß-HB and liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). As well, decreased rates of hepatic fatty acid oxidation correlated with liver HMGCS2 mRNA and serum ß-HB. Our work supports serum ß-HB as a potential marker for hepatic fatty acid oxidation and liver injury during NAFLD.

Hypoalbuminemia as a risk factor for complications in revisional/conversional bariatric surgery: an MBSAQIP analysis.

BACKGROUND: Hypoalbuminemia (HA) is a risk factor for serious complications after elective bariatric surgery. Patients undergoing revisional/conversional bariatric surgery may represent a higher-risk group who often have underlying co-morbid medical illnesses and more complex surgery. OBJECTIVES: This study investigated the postoperative complications in patients with HA undergoing revisional/conversional bariatric surgery. SETTING: Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP), years 2015-2019. METHODS: The MBSAQIP database was used to evaluate patients undergoing non-banding revisional/conversional bariatric surgery between 2015 and 2019. Patients were categorized by serum albumin (≤3.5 g/dL). Variables were assessed via bivariate analysis and multivariable regression. Propensity score matching was conducted to compare gastric bypass (RYGB) to sleeve gastrectomy (VSG). RESULTS: One hundred forty-seven thousand four hundred thirty patients underwent revisional/conversional procedures. After applied exclusions, 58,777 patients were available for analysis. The HA group had a significantly (P < .05) higher prevalence of being black (22.95% versus 17.76%), renal insufficiency (1.08% versus .36%), smoking history (9.47% versus 6.91%), chronic obstructive pulmonary disease (COPD) (2.54% versus 1.33%), and history of deep vein thrombosis (DVT) (4.03% versus 2.3%). Postoperative complications associated with HA included perioperative blood transfusion (3.1% versus 1.27%; P < .001), 30day readmission (10.87 versus 6.77%; P < .001), 30day reoperation (4.9% versus 3.18%; P < .001), and 30day mortality (.40% versus .14%; P < .0001). HA was a significant predictor of 30day readmission in the RYGB versus VSG matched cohort (odds ratio [OR], 1.30; 95% confidence interval [CI], [1.14, 1.48]; P < .001). CONCLUSIONS: HA is a risk factor requiring attention for patients undergoing revisional/conversional bariatric surgery and optimization of nutritional status or medical comorbidities associated with HA prior to bariatric surgery may help avoid postoperative complications.